Encyclopedia
Please note this is a comparison between Version 1 by Konstantinos Tziomalos and Version 2 by Jessie Wu.
Patients with chronic kidney disease (CKD) have a higher risk ofboth ischemic and hemorrhagic stroke. This association appears to be partly independent from the higher prevalence of established risk factors for stroke in patients with CKD, including hypertension and atrial fibrillation.
- chronic kidney disease
- stroke
- hypertension
- dyslipidemia
- thrombosis
1. Atrial Fibrillation and Stroke in Chronic Kidney Disease
Atrial fibrillation (AF) is an established risk factor for stroke [1][64]. Studies have demonstrated a much higher than previously suspected incidence of occult AF among patients with stroke [2][3][65,66].There is a positive relationship between AF and chronic kidney disease (CKD) regarding ischemic stroke risk [4][5][67,68]. A meta-analysis of 25 studies demonstrated that the prevalence of AF was 11.6% and the overall incidence was 2.7/100 patient-years in end stage renal disease (ESRD) patients [6][69]. Another large study found that the incidence rates of AF were 12.1, 7.3, and 5.0 per 1000 person-years in ESRD, CKD, and non-CKD patients, respectively [7][70]. In a study from China, AF was associated with a two-fold increased risk of ischemic stroke and a 325% increased risk of hemorrhagic stroke in patients with CKD [8][71]. Data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS) showed that AF at study enrollment was positively associated with all-cause mortality and stroke [9][72]. The Stockholm CREAtinine Measurements (SCREAM) Project confirmed that AF was associated with a two-fold higher risk of stroke (both ischemic and hemorrhagic) in patients with CKD, and the stroke risk remained similar across all eGFR groups [10][73]. In a large prospective study, decreased eGFR (<45 mL/min per 1.73 m2) correlated with all-cause mortality, stroke recurrence, and greater disability in diabetic and non-diabetic patients with acute stroke followedup for 1 year [11][74]. In a nationwide prospective study in a Chinese population, the associations between low eGFR and risk of recurrent stroke, death, and poor functional outcome in stroke patients with AF were stronger than in those without AF [12][75].
AF and CKD have a bidirectional relationship, with the presence of CKD increasing the risk of incident AF and the presence of AF accelerating the development and progression of CKD [13][14][76,77]. The proposed underlying mechanisms of CKD and AF interaction are activation of the renin-angiotensin-aldosterone system (RAAS), uremic toxins, inflammation, myocardial remodeling and fibrosis, and dysregulated calcium homeostasis [13][15][16][76,78,79]. Up-regulation of the RAAS is involved in cardiac remodeling and may exert direct electrophysiological effects [17][80].
Regarding the management of AF in patients with CKD, a recent meta-analysis of 19 studies (n = 124,628) showed that direct oral anticoagulants (DOACs) reduced both the risk of stroke and major bleeding more than warfarin [18][81]. Among DOACs, apixaban was the safest and most effective in this population [18][81]. Another meta-analysis of eight RCTs and 46 observational studies reached similar conclusions and also reported that both DOACs and warfarin increase the risk of bleeding in patients on dialysis without reducing the risk of stroke versus no anticoagulation [19][82].
2. Prothrombotic State and Stroke in Chronic Kidney KDisease
Non-paroxysmal AF and reduced GFR might predispose to the development of left atrium thrombus found on transesophageal echocardiography [20][21][83,84]. The pathogenetic mechanisms of thrombosis in these patients include platelet activation as well as the effects of uremic toxins on platelets [22][23][24][25][85,86,87,88]. However, platelet dysfunction is a key factor responsible for hemorrhagic complications in advanced kidney disease [22][26][85,89]. Multiple studies have shown that defects in fibrin formation and fibrinolysis serve as thrombogenic factors in CKD (Table 1) [27][28][29][90,91,92].
Table 1.
Pathogenesis of prothrombotic state in chronic kidney disease.
| Type of Study | Population | n | Findings | Ref. |
|---|---|---|---|---|
| Left atrial thrombus formation | ||||
| Observational | Patients undergoing transesophageal echocardiography | 581 | Every 10 mL/min/1.73 m2 decrease in estimated glomerular filtration rate correlated with left atrial thrombogenic milieu | [23][86] |
| Observational | Patients with AF | 1033 | GFR < 56 mL/min/1.73 m2 was an independent predictor of left atrial thrombus | [22][85] |
| Platelet activation | ||||
| Animal study | Mice with CKD | Not applicable | Platelet hyperactivation was found in mice with CKD and was associated with high levels of serum indoxylsulfate | [25][88] |
| Observational | Patients on clopidogrel undergoing percutaneous coronary intervention | 8410 | Two-fold higher odds for high platelet reactivity associated with a creatinine clearance < 30 mL/min compared with ≥60 mL/min | [26][89] |
| Fibrin formation and lysis | ||||
| Cross-sectional | Patients with AF | 502 | Impaired fibrinolytic capacity in patients with stages 3 to 4 CKD compared with controls | [29][92] |
| Cross-sectional | Patients with AF, with and without CKD, and healthy controls | 56 | Reduced eGFR was associated with reduced latency time and time to achieve maximum clot thickness | [30][93] |
| Cross-sectional | Patients with end-stage renal disease (ESRD) and controls | 316 | In ESRD, both time required to form (491 ± 177 vs. 378 ± 96 s, p < 0.001) and to lyse an occlusive platelet thrombus were prolonged (1820 vs. 1053 s, p < 0.001) | [31][94] |
| Cross-sectional | Patients undergoing hemodialysis, renal transplant recipients, and healthy controls | 84 | Increased platelet aggregability in CKD patients | [26][89] |
3. Dyslipidemia and Stroke in Chronic Kidney KDisease
Patients with CKD are characterized by a specific lipid profile termed “uremic dyslipidemia”, which corresponds to nearly normal low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), and high triglyceride levels [32][104]. During a 3-year follow-up in patients with stage 3 CKD receiving statin treatment, the group with LDL-C levels between 70 and 100 mg/dL exhibited lower risk of ischemic stroke and intracerebral hemorrhage compared with patients with LDL-C levels ≥ 100 mg/dL. In contrast, compared with patients with LDL-C levels ≥ 100 mg/dL, those with LDL-C levels < 70 mg/dL had lower risk of ischemic stroke but no difference in intracerebral hemorrhage [33][105].Compared with non-CKD patients in the lowest LDL-C quartile, the multivariable-adjusted risk of severe stroke increased 2.9-fold (95% CI 1.48–5.74) in patients with CKD in the highest LDL-C quartile [34][106]. A meta-analysis demonstrated that as eGFR declines, there is a trend for smaller relative risk reduction for major coronary events and stroke with statin therapy, even after adjusting for smaller reductions in LDL-C levels in patients with more advanced CKD [35][107]. In a meta-analysis of six RCTs with 10,993 patients with CKD, the stroke rate was reduced in the high-intensity statin therapy group [36][108]. As the CKD stage deteriorates, statins appear to have no effect on ischemic and hemorrhagic stroke [37][109]. Uremia leads to several modifications of the structure of HDL, which has an adverse effect on its functionality [38][110].
4. Carotid Atherosclerosis and Stroke in Chronic Kidney KDisease
In observational studies, deterioration in renal function was independently associated with increased carotid intima-media thickness (cIMT) [39][40][111,112]. cIMT and eGFR were inversely correlated in patients with stroke, whilemean cIMT, plaque size, and internal carotid artery stenosis were associated with symptomatic ischemic stroke [41][113]. Furthermore, decreased kidney function was associated with a faster increase in carotid cIMT [42][114]. Similar findings were observed in a 4-year study that reported an increase in cIMT with decreasing eGFR in CKD patients [43][115]. However, proteinuria and eGFR were associated with cIMT but not with the presence of calcified plaque in patients with mild or moderate CKD [44][116]. Moreover, eGFR was negatively correlated with the degree of carotid stenosis (r = 0.03; p < 0.05) in patients with acute stroke [45][117]. In contrast, another study did not demonstrate a difference in carotid atherosclerosis between CKD and healthy individuals [46][118]. It has been suggested that atherosclerosis is associated with increased levels of endotoxin and inflammatory markers [47][48][49][119,120,121]. The atheromatous lesions of CKD patients were also more frequently unstable or ruptured more often compared with patients without CKD [50][51][122,123].
5. Uremic Toxins and Stroke in Chronic Kidney KDisease
Uremic toxins can induce a number of cardiac and vascular abnormalities, including cardiac fibrosis, atherosclerosis, thrombosis, vascular calcification, and microvascular rarefaction, which lead to stroke and other CVD complications [52][124]. Patients with CKD are exposed to systemically derived toxins such as asymmetric dimethylarginine (ADMA), homocysteine, thiocyanate, tumor-necrosis factor α, and interleukin 6 [53][125]. CKD and uremic toxins potentiate cerebral tissue activation through inflammatory and oxidative pathways, inhibition of antioxidant and cytoprotective systems, and erosion of cerebral capillary junctional complex—events that contribute to central nervous system dysfunction and impaired blood–brain barrier [54][55][56][57][126,127,128,129]. It has been suggested that disruptions of the blood–brain barrier and edema formation both participate in the development of neurological dysfunction in acute and chronic cerebral ischemia [58][130].
6. Anemia, Erythropoietin Stimulating Agents, and Stroke in Chronic Kidney KDisease
In a meta-analysis of 24 RCTs, in the high hemoglobin target vs. low hemoglobin target trials, there was a hi
In a meta-analysis of 24 RCTs, in the high hemoglobin target vs. low hemoglobin target trials, there was a higher risr risk of stroke in the high hemoglobin target groups both in non-dialysis and dialysis CKD patients [59][131]. However, in another meta-analysis of 13 RCTs in predialysis CKD patients, no significant difference was found in stroke rates between the higher hemoglobin group and the lower [60][132]. Moreover, despite an association between low hemoglobin concentrations and a high risk of hemorrhagic stroke, no correlation with ischemic stroke was found in patients undergoing hemodialysis [61][133]. A higher erythropoietin resistance was associated with an increased risk of brain hemorrhage, but not with brain infarction, in patients receiving maintenance hemodialysis [62][134]. In a large national sample of anemic patients with CKD, treatment with erythropoietin-stimulating agents was associated with an increased risk of acute stroke [63][135]. On the contrary, increased risks of stroke and its subtypes were not reported with even large annual defined daily doses of erythropoietin in CKD [64][136]. Current guidelines suggest caution when initiating erythropoietin-stimulating agents in CKD patients with high risk of stroke [65][137].
7. Hyperphosphatemia and Stroke in Chronic Kidney KDisease
Dysregulation of calcium and phosphate metabolism is common in CKD patients, and results in vascular calcification [64][136]. In an attempt to explain the phenomenon of vascular calcification under hyperphosphatemic conditions, several studies showed that elevated serum phosphate levels directly drive vascular smooth muscle cells to undergo phenotypic changes that predispose to calcification [65][66][67][137,138,139]. An observational study demonstrated that phosphate levels are associated with the coexistence of subclinical atheromatosis in non-dialysis CKD patients [68][140]. Notably, even phosphate levels within the normal range were associated with an increased risk of subclinical atheromatosis in men, whereas in women this risk only increased with serum levels above the upper limit of normal [68][140]. Data from the NEFRONA study suggested that the presence of atheromatic plaque was associated with high phosphate levels in stage 4–5 CKD but there was a U-shaped association in patients on dialysis [69][141]. Higher serum phosphate levels were associated with an increased risk of brain hemorrhage, whereas low levels were associated with an increased risk of brain infarction in hemodialysis patients followed-up for a median of 3.9 years [70][142]. In a small observational study, patients undergoing dialysis with serum phosphate levels < 4.5 mg/dL had a 3.40-fold higher risk of ischemic stroke in comparison with patients with average serum phosphate levels ≥ 4.5 mg/dL [71][143]. However, other studies did not show an association between phosphate levels and risk of ischemic and hemorrhagic stroke in hemodialysis patients [72][73][144,145]. Apart from phosphorus, biomolecules involved in mineral bone disease such as fibroblast growth factor-23 and klotho are associated with the incidence of stroke [74][75][146,147].
