How Can CKD Patients Prevent Stroke?

Patients with chronic kidney disease (CKD) are at higher risk of ischemic and hemorrhagic stroke than healthy people. After adjustment for confounders, both acute kidney injury (AKI) and CKD were independently associated with stroke onset and poor outcomes. So, what kind of intervention can help reduce the risk of stroke and improve the poor prognosis of CKD patients?

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On February 8, 2023, NDT published a review from France, which analyzed the risk of stroke in patients with kidney disease at various stages, and clarified the effect of surgery and drugs on the prevention and treatment of stroke in CKD patients. It is worth noting that carotid endarterectomy, anticoagulation and thrombolysis, and sodium-glucose cotransporter 2 inhibitors (SGLT-2i) can all improve the risk of stroke in patients with kidney disease or be used for treatment after stroke, but Patients need to be carefully screened before the benefits outweigh the risks. In addition, there are two potential prevention methods that deserve the attention of doctors.

Stroke risk in patients with various stages of kidney disease

1 CKD

Stroke is the third leading cause of cardiovascular death in CKD patients. Some studies and Meta-analysis have shown that an estimated glomerular filtration rate (eGFR)<60ml/min/1.73㎡ is closely related to a 43% increased risk of stroke. In addition, multiple studies have highlighted a positive association between worsening renal function and stroke mortality. The post-stroke mortality rate of non-CKD patients was 10%, while that of CKD patients was 30%. After adjusting confounding factors, the relative risk of death (aHR) of CKD patients ranged from 1.5 to 2.1. Studies have also suggested that CKD patients have an increased risk of long-term mortality after stroke.

A prospective study in the United Kingdom found that patients with even mild renal impairment had an increased risk of stroke. After adjusting confounding factors such as age, diabetes, and hypertension, compared with patients with serum creatinine<116umol patients="" with="" serum="" creatinine="">116umol/L had a higher risk of poor prognosis after stroke (aRR = 1.6; 95% CI, 1.1~2.1). A prospective cohort study by Shimizu et al. found that in Japanese CKD patients, both men and women had a higher risk of hemorrhagic stroke, and the risk of hemorrhagic stroke was higher in female patients than in male patients. In addition to death, CKD patients are also at increased risk of cognitive impairment after stroke, but CKD is not independently associated with cognitive impairment.

2 ESKD

End-stage kidney disease (ESKD) is associated with increased stroke incidence and poorer outcomes. In a large US cohort study of 69,371 ESKD cases, the incidence rates of ischemic and hemorrhagic stroke were 21.1 and 4.7 per 1000 patient-years, respectively, compared with 3.3 per 1000 global Patient-years and 0.5/per 1000 patient-years. Similar to patients with CKD, patients with ESKD are at higher risk of death after an ischemic or hemorrhagic stroke. Even after adjusting for confounding factors, ischemic and hemorrhagic stroke-related mortality rates were 17.9% and 53.4%, respectively, three times higher than in the general population. Of note, anticoagulant therapy does not appear to reduce stroke risk in patients with ESKD.

3 Kidney transplant recipients and pediatric patients

Multiple studies have found that kidney transplant recipients have a significantly lower risk of ischemic and hemorrhagic stroke compared with patients with ESKD. One study found that compared with propensity-matched ESKD patients, after adjusting for age, sex, and comorbidities, the risk of all strokes was 60% lower, and the risk of ischemic and hemorrhagic stroke was 48% lower and 72% lower, respectively. However, after the transplanted kidney fails, the risk of stroke increases significantly. Although rare in pediatric patients with kidney disease, available data suggest that children with CKD are at higher risk of stroke than children without CKD and that stroke is associated with poorer cognitive performance.

Risk factors for stroke in CKD patients

The risk factors for stroke in CKD patients can be divided into two categories, namely traditional risk factors and specific risk factors for patients with renal disease. Traditional risk factors include hypertension, diabetes, dyslipidemia, atrial fibrillation, major arteriosclerosis/calcification; risk factors specific to patients with the renal disease include acute kidney injury (AKI), systemic and neuroinflammation, blood-brain barrier dysfunction, uremia Accumulation of symptomatic toxins and impairment of coagulation and thrombus balance (Figure 1). Although CKD patients generally have traditional risk factors for stroke, it is not enough to explain the current clinical situation and needs to be analyzed in combination with the unique risk factors of kidney disease patients. Physicians should intervene in the traditional and specific risk factors of patients with renal disease, such as reducing blood pressure, the risk of AKI, and the level of uremic toxins to prevent stroke.

Current prevention and control methods

Since most patients with kidney disease have a higher risk of stroke, in addition to intervening risk factors, there are three current prevention and treatment methods worthy of doctors' attention: ①carotid endarterectomy; ②anticoagulant therapy and thrombolysis; ③SGLT- 2i.

1 Carotid endarterectomy

Narrowing of large arteries is often caused by atherosclerosis and is an important cause of ischemic stroke. It is worth noting that the prevalence of large artery stenosis in China is as high as 47%. Existing evidence shows that CKD increases the stiffness, diameter, intima-media thickness, and elastic modulus of the carotid artery, which in turn makes the brain of CKD patients more sensitive to blood pressure and prone to hypertension-related cardiovascular events. In the middle-aged and elderly population, CKD is independently associated with cranial artery stenosis. Even elderly proteinuric patients with normal renal function have increased carotid intima-media thickness.

In terms of treatment, statins appear to be less effective at improving carotid atherosclerosis than carotid endarterectomy. However, major adverse events are also more likely to occur in patients with CKD after carotid endarterectomy than in patients with normal renal function. The study by Kalrin et al. showed that carotid endarterectomy could significantly improve stroke-free survival in patients with CKD if carefully selected, especially in patients with symptomatic CKD. A recent study also showed that for patients with ESKD, carotid endarterectomy and carotid artery stenting were associated with a 4-fold increase in mortality. Therefore, whether to use carotid endarterectomy is closely related to the individual conditions of the patient, such as renal function and vascular status. Patients undergoing surgery should be carefully selected and the risk-benefit ratio should be considered comprehensively.

2 Anticoagulation and thrombolysis

Cardiac embolism is the cause of 14% to 30% of ischemic strokes and is referred to as cardioembolic stroke (CES). In CKD patients, CES is more common, accounting for 33% to 38% of strokes. After adjusting for confounding factors such as age, hypertension, and diabetes, both lower eGFR and proteinuria were associated with CES. In the general population, the treatment option for CES is warfarin anticoagulation. However, Kumar et al. showed that anticoagulant therapy may also be associated with a 2.6-fold increased risk of ischemic stroke in patients >65 years of age with CKD. A recent meta-analysis showed that oral anticoagulants are superior to warfarin in preventing thromboembolic events, and for CKD patients with GFR>15ml/min, oral anticoagulants have a lower bleeding risk than warfarin Forest. However, this does not apply to dialysis patients, as anticoagulant therapy increases the risk of bleeding and adverse outcomes in patients. Whether anticoagulant therapy can be used to prevent thromboembolism in patients with CKD stage 4-5 is still a controversial topic. There is currently no evidence of specific benefits of this therapy for this population, but an increased risk of bleeding is inevitable.

Furthermore, few studies have specifically investigated the response to therapy, namely thrombolysis, and thrombectomy, in patients with ischemic stroke in CKD. Currently, the evidence for thrombolysis and thrombectomy is unclear and conflicting. A retrospective study by Agrawal et al. found that after 3 months of thrombolytic therapy, there was no significant difference in the risk of bleeding, death, and functional prognosis between patients with eGFR<60ml and="" egfr="">60ml/min/1.73㎡. The difference is that CKD patients can be treated with thrombolysis and thrombectomy after stroke. However, a US study of 179,710 patients with ischemic stroke found that compared with non-CKD patients, patients with CKD were less likely to receive intravenous thrombolysis or thrombectomy and were associated with poorer prognoses. There are also retrospective studies showing that impaired renal function is an independent predictor of poor prognosis after 3 months of intravenous thrombolysis. These studies suggest that patients with CKD may be at higher risk of intracerebral hemorrhage, disability, neurologic injury, and death after thrombolysis. Scholars suggest that thrombolysis and thrombectomy may not be suitable for all CKD patients.

3 SGLT-2i

Interestingly, a recent meta-analysis showed that in patients with CKD and diabetes, SGLT-2i reduced the risk of ischemic and hemorrhagic stroke by 32% compared with placebo, but in diabetic patients without CKD. But it doesn't work. The CREDENCE study showed that canagliflozin can significantly reduce the risk of stroke in CKD patients (eGFR 30-45ml/min/1.73㎡) (OR = 0.46; 95% CI, 0.24-0.87). Meta-analysis also showed that SGLT-2i can reduce the risk of stroke in all patients with eGFR<45 ml/min/1.73㎡. The DAPA-CKD study found that dapagliflozin can reduce the risk of cardiovascular events in CKD patients, but the risk of stroke was not specifically evaluated. In addition to benefiting the cardiovascular system, SGLT-2i can also reduce the level of proteinuria in patients and benefit the renal function of patients.

Potential treatment modalities after stroke

Very little research has been done on the impact of decreased renal function on stroke outcomes, but preclinical studies suggest that metformin may prevent stroke injury in CKD mice. Compared with non-CKD mice, CKD mice had larger cerebral infarct volume, more neurological damage, and increased neuronal apoptosis after stroke. Metformin can reduce the volume of cerebral infarction, the degree of nerve injury, and the apoptosis of neurons after ischemia in CKD mice. Notably, neurological outcomes were better in CKD mice when they were diabetic.

In addition to metformin, lowering the levels of uremic toxins also prevents stroke in patients with CKD. Take indyl sulfate (IS) as an example, which has endothelial toxicity. One study found that in patients with CKD, AST-120 (which is charcoal in nature and acts as an oral adsorbent for uremic toxins) reduced stroke risk by 10% and 26% at 3 and 5 years, respectively. However, AST-120 can also non-specifically adsorb intestinal substances, so it is not marketed in the European Union and the United States and is only sold in Japan2.

In general, CKD patients have a higher risk of stroke than healthy people, and the prognosis is poor. In addition to intervening risk factors, there are currently 3 ways to prevent stroke in CKD patients, they are ①carotid endarterectomy, ②anticoagulant therapy, and thrombolysis, ③SGLT-2i. In addition, metformin and AST-120 may be potential prevention and treatment methods for CKD stroke, which deserve everyone's attention.

for more information: Ali.ma@wecistanche.com