- Email: [email protected]
Chronic Kidney Disease and Outcome Following Endovascular Thrombectomy for Acute Ischemic Stroke
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Chronic Kidney Disease and Outcome Following Endovascular Thrombectomy for Acute Ischemic Stroke Luke J. Sutherland, MBChB,* William K. Diprose, MBChB,†,‡ Michael T.M. Wang, MBChB,† and P. Alan Barber, MBChB, PhD, FRACP†,‡ Background and Objectives: Chronic kidney disease (CKD) is present in 20% to 35% of acute ischemic stroke patients and may increase the risk of poor functional outcome or death. We aimed to determine whether CKD was associated with worse outcome in stroke patients treated with endovascular thrombectomy (EVT). Design, Setting, Participants, and Measurements: Consecutive EVT patients were identified from a prospective registry and dichotomized into patients with and without CKD, defined as an eGFR of less than 60 mL/min/1.73m2. The primary outcome was 3-month mortality following EVT. Secondary outcomes included symptomatic intracerebral hemorrhage (defined by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study), early neurological recovery (defined as change in National Institutes of Health Stroke Scale [NIHSS] score of 8 at 24 hours or an NIHSS of 0-1 at 24 hours) and functional independence (defined as a modified Rankin Scale [mRS] score of 0, 1 or 2) at 3 months. Results: 378 EVT patients (223 men; mean § SD age 65 § 15 years) were included. The median (IQR) admission eGFR was 71 (58-89) mL/min/1.73 m2 and 117 (31%) patients had CKD. Multiple logistic regression adjusted for potential confounders demonstrated that CKD was a significant predictor of lower rates of functional independence (OR = .54, 95% CI, .31 to .90, P = .02), higher mRS scores (common OR = 1.78, 95% CI, 1.14 to 2.81, P = .01), and increased mortality (OR = 2.19, 95% CI, 1.16 to 4.12, P = .01). There was no association between CKD and early neurological recovery (OR = .92, 95% CI, .55 to 1.49, P = .71) or symptomatic intracerebral hemorrhage (OR = 1.18, 95% CI, .38 to 3.69, P = .77). Conclusions: CKD was a significant predictor of worse functional outcome and mortality in stroke patients treated with EVT. The presence of CKD should not preclude patients from proceeding to EVT, but may help with prognostication and improve shared decision-making between patients, families and physicians. Key Words: Chronic kidney disease—acute stroke—endovascular thrombectomy— nephrology © 2020 Elsevier Inc. All rights reserved.
Introduction From the *Department of Renal Medicine, Auckland City Hospital, Auckland, New Zealand; †Department of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; and ‡Department of Neurology, Auckland City Hospital, Auckland, New Zealand. Received November 13, 2019; revision received January 6, 2020; accepted January 11, 2020. Funding: The Neurological Foundation of New Zealand funds a Clinical Fellowship for Dr William Diprose. Address correspondence to P. Alan Barber, MBChB, PhD, FRACP, Department of Medicine, Faculty of Medical and Health Sciences, The University, of Auckland, Private Bag 92019, Auckland 1142. E-mail: [email protected]. 1052-3057/$ - see front matter © 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104665
Chronic kidney disease (CKD) increases the risk of stroke,1-6 and is present in 20% to 35% of acute ischemic stroke patients when defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2.7 Up to half of patients presenting with stroke with evidence of pre-existing CKD are unaware of this diagnosis.8 Maintenance hemodialysis patients also have a higher incidence of stroke, which is a major cause of death in these patients.9 Causes of increased stroke risk in CKD patients include vascular calcification, autonomic dysfunction, hyperhomocysteinemia, intradialytic volume shifts and vertebrobasilar steal from arteriovenous fistulae.10 There may also be lower use of pharmacotherapies, such as
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novel oral anticoagulants in CKD patients with atrial fibrillation.11 Patients treated with endovascular thrombectomy (EVT) are exposed to greater contrast volumes as a result of digital subtraction angiography than other stroke patients, and this may increase the risk of contrast-associated acute kidney injury, particularly in those with pre-existing CKD.12 In EVT patients, one study reported that CKD was associated with increased mortality but not with functional outcome or symptomatic intracerebral hemorrhage.13 We aimed to further define the relationship between CKD and outcome in stroke patients treated with EVT.
Methods Consecutive patients from a single-center prospective EVT registry between March 2011 and March 2019 were included if they had baseline creatinine measurements and follow-up data available. The study center is a tertiary hospital which provides EVT services to approximately 2.8 million people. The registry contains data regarding patient demographics, medical comorbidities, clinical and imaging features of the stroke, treatment details and patient outcomes. This study was approved by the institutional review board. All analyses were performed on deidentified data and the study was considered low risk, so informed consent was not required. Baseline and 24-hour stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) by the attending stroke team.14 The Alberta Stroke Program Early CT Score was used to assess the size of baseline infarct. 15 Successful recanalization was defined as a modified Thrombolysis in Cerebral Infarction (mTICI) score of 2b to 3.16 The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate estimated glomerular filtration rate (eGFR).17 Patients were dichotomized into patients with and without CKD, defined as an eGFR of less than 60 mL/min/1.73 m2.18 The primary outcome was 3-month mortality following EVT. Secondary outcomes included symptomatic intracerebral hemorrhage (defined by the Safe Implementation of Thrombolysis in StrokeMonitoring Study definition), early neurological recovery (defined as change in NIHSS of 8 at 24 hours or an NIHSS of 0-1 at 24 hours), functional independence at 3 months (defined as a modified Rankin Scale [mRS] score of 0, 1 or 2) and mRS at 3 months.19 Statistical analysis was performed using IBM SPSS Statistics version 25.0 (New York) and GraphPad Prism version 6.02 (California). Preliminary univariate logistic or ordinal regression and Fisher’s exact tests were used to identify potential clinical predictors of outcome measures. The relationship between CKD (defined as an eGFR < 60 mL/min/1.73 m2) and outcome measures was then assessed using multiple logistic or ordinal regression, incorporating relevant variables with P < .15 from the univariate analysis. The number of variables used in the
multivariable regression analysis was approximately limited to the number of adverse events divided by 10, to avoid overfitting. All tests were 2-tailed and P < .05 was considered statistically significant.
Results A total of 393 patients were screened for eligibility, 6 were excluded due to the absence of baseline creatinine measurements, and 9 were excluded due to the absence of follow-up data. There were 378 patients (223 men; mean § SD age 65 § 15 years, median [IQR] baseline NIHSS score of 17 [12-21]) included in the analysis (Table 1). 205 (54%) patients received intravenous therapy with alteplase. Successful recanalization (mTICI 2b-3) was achieved in 332 (88%) patients. The median (IQR) admission creatinine level was 88 (72-104) mmol/L and the median (IQR) eGFR was 71 (58-89) mL/min/1.73 m2. 117 (31%) patients had CKD. Patients with CKD were more likely to be older and have hypertension, hyperlipidemia, coronary artery disease and atrial fibrillation. Symptomatic intracerebral hemorrhage occurred in 16 (4%) patients. 182 (48%) patients exhibited early neurological improvement. At 3 months, 215 (57%) patients achieved functional independence and 58 (15%) had died. Unadjusted univariate and multivariable-adjusted odds ratios of outcome measures by admission renal function are presented in Table 2 and the distribution of 3-month mRS scores are illustrated in Figure 1. Multiple logistic regression adjusted for potential confounders demonstrated that CKD was associated with lower rates of functional independence (odds ratio [OR] = .54, 95% confidence interval [CI], .31 to .90, P = .02), higher mRS scores (common OR = 1.78, 95% CI, 1.14 to 2.81, P = .01), and increased mortality (OR = 2.19, 95% CI, 1.16 to 4.12, P = .01). There was no association between CKD and early neurological recovery (OR = .92, 95% CI, .55 to 1.49, P = .71) or sICH (OR = 1.18, 95% CI, .38 to 3.69, P = .77). Subgroup analysis conducted according to baseline eGFR stratification based on the stages of chronic kidney disease are presented in Table 3 and demonstrated similar trends, although increased mortality were limited to patients with a baseline eGFR of <30 mL/min/1.73 m2 (OR = 5.72, 95% CI, 1.41 to 21.34, P = .01).
Discussion Ischemic stroke patients treated with EVT who had CKD had lower rates of functional independence and were more likely to have died at 3 months. Patients with CKD were older and had higher rates of cardiovascular risk factors. These results are in contrast to an earlier study of stroke patients treated with EVT where an association was found between lower eGFR and higher rates of death but no association with functional independence or mRS scores.13 Neither study found an association between eGFR and symptomatic intracerebral hemorrhage. Similarly, a large
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Table 1. Baseline patient, procedure and outcome measures Parameters
All (n = 378)
eGFR < 60 (n = 117)
eGFR 60 (n = 261)
65 § 15 223 (59%)
74 § 11 70 (60%)
61 § 15 153 (59%)
74 (20%) 254 (67%) 175 (46%) 165 (44%) 66 (17%) 185 (49%)
28 (24%) 98 (84%) 67 (57%) 45 (38%) 30 (26%) 70 (60%)
46 (18%) 156 (60%) 108 (41%) 120 (46%) 36 (14%) 115 (44%)
0 (0-0) 154 § 28 17 (12-21) 9 (7-10) 309 (82%) 88 (72-104) 71 (58-89) 205 (54%)
0 (0-0) 157 § 27 18 (12-21) 9 (8-10) 99 (85%) 113 (101-129) 52 (41-56) 65 (56%)
0 (0-0) 153 § 28 17 (11-21) 9 (7-10) 210 (80%) 77 (66-89) 82 (70-94) 140 (54%)
332 (88%) 215 (165-310) 280 (225-385)
105 (90%) 215 (170-310) 275 (225-370)
227 (87%) 215 (165-315) 285 (225-390)
182 (48%) 14 (4%) 2 (1-4) 215 (57%) 58 (15%)
54 (46%) 5 (4%) 3 (1-5) 55 (47%) 27 (23%)
128 (49%) 9 (3%) 2 (1-3) 160 (61%) 31 (12%)
Age, yr, mean§SD Men, n (%) Risk factors Diabetes, n (%) Hypertension, n (%) Dyslipidemia, n (%) Smoking, n (%) Coronary artery disease, n (%) Atrial fibrillation, n (%) Baseline Prestroke mRS, median (IQR) Systolic blood pressure, mmHg, mean § SD NIHSS, median (IQR) ASPECTS, median (IQR) Anterior circulation occlusion site, n (%) Creatinine, mmol/L, median (IQR) eGFR, mL/min/1.73 m2, median (IQR) IV alteplase, n (%) Procedure mTICI 2b-3 recanalisation, n (%) LKN to puncture, mins, median (IQR) LKN to procedure completion, mins, median (IQR) Outcomes 24-hr early neurological improvement, n (%) sICH, n (%) 3-mon mRS, median (IQR) 3-mon functional independence, n (%) 3-mon mortality, n (%)
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; eGFR, estimated glomerular filtration rate; LKN, last known normal; mRS, modified Rankin Score; mTICI, modified Thrombolysis in Cerebral Infarction; NIHSS, National Institutes of Health Stroke Scale; and sICH, symptomatic intracerebral.
study of 44,410 stroke patients treated with intravenous thrombolysis, of whom 34% had an eGFR less than 60 mL/ min/1.73 m2, also found no association between CKD and symptomatic intracerebral hemorrhage.20 As well as an increased risk of ischemic stroke, lower eGFR is associated with increased risk of poor outcome, symptomatic intracerebral hemorrhage and death in stroke patients treated with intravenous thrombolysis (26%-32% of whom had an eGFR < 60 mL/min/1.73 m2).21,22 A recent analysis by our group found that CKD is associated with an increased risk of contrast-associated acute kidney injury (CA-AKI) in patients receiving EVT, and this in turn was associated with increased mortality (OR 4.68, 95% CI, 1.05-20.97; P = .04).23 The rate of CA-AKI was low, however, occurring in only 3.3% of patients. As a result, the confidence intervals for the association with increased mortality were unstable. CKD is also independently associated with worse functional outcomes after intracerebral
hemorrhage,24-28 and in patients with an acute coronary syndrome.29 How CKD confers increased risk of poor outcome in stroke patients treated with EVT is unclear. CKD patients are generally older and have other comorbidities such as hypertension, atrial fibrillation and ischemic heart disease, as seen in this study.22 Worsening eGFR may result in atherosclerosis, vascular calcification, anemia, oxidative stress, hyperhomocysteinemia and coagulation changes, increasing the risk of both stroke and worse outcomes following stroke.30,31 CKD results in accelerated chronic microvascular damage, which may impair the ability of the brain to recover from an acute ischemic insult, similar to that seen in EVT patients with cerebral atrophy or chronic hyperglycemia.32-34 Indeed, CKD patients have more extensive white matter lesions and reduced deep white matter volume.35 Finally, CKD patients with atrial fibrillation are less likely to be treated with novel oral
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Table 2. Logistic regression odds ratios of outcome measures by renal function Univariate logistic regression eGFR < 60
OR (95% CI)
24-hr early neurological improvement* sICHy 3-mon mRSz 3-mon functional independencex 3-mon mortality║
.89 (.58 to 1.38) 1.25 (.41 to 3.81) 1.76 (1.21 to 2.59) 0.56 (.36 to .87) 2.23 (1.26 to 3.94)
Multiple logistic regression
P value
OR (95% CI)
P value
.62 .69 .004 .009 .006
.92 (.55 to 1.49) 1.18 (.38 to 3.69) 1.78 (1.14 to 2.81) .54 (.31 to .90) 2.19 (1.16 to 4.12)
.71 .77 .01 .02 .01
Abbreviations: 95% CI, 95% confidence interval; mRS, modified Rankin Score; OR, odds ratio; and sICH, symptomatic intracerebral hemorrhage. *Multivariable analyses adjusted for age, diabetes, atrial fibrillation, baseline NIHSS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. † Multivariable analyses adjusted for diabetes, and coronary artery disease. ‡ Multivariable analyses adjusted for age, hypertension, diabetes, coronary artery disease, baseline mRS, baseline NIHSS, baseline ASPECTS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. § Multivariable analyses adjusted for age, hypertension, diabetes, coronary artery disease, baseline mRS, baseline NIHSS, baseline ASPECTS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. ║ Multivariable analyses adjusted for age, coronary artery disease, baseline NIHSS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation.
anticoagulants, and stroke patients with atrial fibrillation tend to have worse outcomes.36 Despite finding lower rates of functional independence and higher rates of mortality in these patients, we do not advocate withholding EVT in stroke patients with CKD. Previous studies have demonstrated the therapeutic benefit of EVT in CKD patients.37 In the cardiology literature, individuals with CKD have inappropriately low rates of coronary angiography, previously referred to as “renalism”.38 At our institution, low GFR is not an exclusion criterion for EVT and we could find no evidence that these patients were less likely to be offered EVT.
Limitations The data in this study are based on a modest sized cohort of consecutive, unselected patients presenting with stroke who proceeded to EVT. The single-center retrospective design has the potential to introduce selection bias and limit the generalizability of the findings. Most patients had been transferred for EVT from other hospitals and we were therefore limited to the data captured in our database. Despite the use of multivariable-adjusted logistic regression techniques, the potential for residual confounding from other unidentified factors cannot be
Figure 1. Distribution of 3-month mRS scores by renal function.
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Table 3. Logistic regression odds ratios of outcome measures by baseline eGFR stratification Univariate logistic regression OR (95% CI)
P value
Multiple logistic regression OR (95% CI)
P value
24-hr early neurological improvement* Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90
.91 (.55 to 1.52) .89 (.50 to 1.56) .54 (.17 to 1.75)
.91 .89 .54
.93 (.50-1.69) .92 (.45-1.94) .68 (.19 to 2.40)
.78 .86 .59
sICHy Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90
1.85 (.38-9.08) 1.76 (.31-9.83) 3.35 (.28-39.56)
.45 .52 .34
1.73 (.35-8.58) 1.61 (.28-9.03) 2.33 (.19-28.94)
.51 .60 .52
1.89 (1.20-2.99) 2.35 (1.42-3.90) 7.92 (2.82-22.19)
.006 .001 <.001
1.86 (1.12-3.22) 2.31 (1.26-4.19) 6.02 (1.92-18.87)
.02 .007 .002
.45 (.20 to .95) .40 (.16 to .86) .12 (.02 to .61)
.04 .02 .01
3-mon mRSz Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90 3-mon functional independencex Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90
.42 (.24 to .74) .36 (.19 to .66) .10 (.02 to .37)
.002 .001 .001
3-mon mortality║ Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90
1.30 (.57 to 2.96) 2.28 (.98 to 5.27) 6.67 (1.89 to 23.57)
.53 .06 .003
1.35 (.55-3.34) 2.34 (.93 to 5.94) 5.72 (1.41 to 21.34)
.51 .08 .01
Abbreviations: 95% CI, 95% confidence interval; mRS, modified Rankin Score; OR, odds ratio; and sICH, symptomatic intracerebral hemorrhage. *Multivariable analyses adjusted for age, diabetes, atrial fibrillation, baseline NIHSS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. † Multivariable analyses adjusted for diabetes, and coronary artery disease. ‡ Multivariable analyses adjusted for age, hypertension, diabetes, coronary artery disease, baseline mRS, baseline NIHSS, baseline ASPECTS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. § Multivariable analyses adjusted for age, hypertension, diabetes, coronary artery disease, baseline mRS, baseline NIHSS, baseline ASPECTS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. ║ Multivariable analyses adjusted for age, coronary artery disease, baseline NIHSS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation.
completely excluded. We were also not able to determine whether the baseline creatinine levels reflected pre-existing CKD or a concurrent acute kidney injury.
shared decision-making between patients, families and physicians.
Acknowledgments Conclusion This study has found an association between CKD and worse outcomes in acute ischemic stroke patients treated with EVT. The presence of CKD should not preclude patients from proceeding to EVT but considering baseline eGFR may improve prognostication and
The authors wish to acknowledge the The Neurological Foundation of New Zealand and The Julius Brendel Trust for their help in facilitating this research.
Conflict of Interest None.
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References 1. Abramson JL, Jurkovitz CT, Vaccarino V, et al. Chronic kidney disease, anemia, and incident stroke in a middleaged, community-based population: the ARIC Study. Kidney Int 2003;64:610-615. 2. Toyoda K. Cerebrorenal interaction and stroke. Contrib Nephrol 2013;179:1-6. 3. Khella SL. New insights into stroke in chronic kidney disease. Adv Chronic Kidney Dis 2008;15:338-346. 4. Tsukamoto Y, Takahashi W, Takizawa S, et al. Chronic kidney disease in patients with ischemic stroke. J Stroke Cerebrovasc Dis 2012;21:547-550. 5. Olesen JB, Lip GYH, Kamper A-L, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367:625-635. 6. Koren-Morag N, Goldbourt U, Tanne D. Renal dysfunction and risk of ischemic stroke or TIA in patients with cardiovascular disease. Neurology 2006;67:224-228. 7. Kdigo CKD, Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150. 8. Kumar V, Krishna P, Naresh S, et al. Stroke in chronic kidney disease. Indian J Nephrol. 2009;19:5. 9. Hojs Fabjan T, Hojs R. Stroke and renal dysfunction. Eur J Intern Med 2014;25:18-24. 10. Toyoda K, Fujii K, Fujimi S, et al. Stroke in patients on maintenance hemodialysis: a 22-year single-center study. Am J Kidney Dis 2005;45:1058-1066. 11. Washam JB, Holmes DN, Thomas LE, et al. Pharmacotherapy for atrial fibrillation in patients with chronic kidney disease: insights From ORBIT-AF. J Am Heart Assoc 2018;18. 7. 12. Mehran R, Dangas GD, Weisbord SD. Contrast-associated acute kidney injury. N Engl J Med 2019;380: 2146-2155. 13. Laible M, M€ ohlenbruch MA, Pfaff J, et al. Influence of renal function on treatment results after stroke thrombectomy. Cerebrovasc Dis 2017;44:351-358. 14. Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke 1994;25:2220-2226. 15. Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. Lancet 2000;355:1670-1674. 16. Zaidat OO, Yoo AJ, Khatri P, et al. Recommendations on angiographic revascularization grading standards for acute ischemic stroke. Stroke 2013;44:2650-2663. 17. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum Creatinine and Cystatin C. N Engl J Med 2012;367:20-29. 18. Andrassy KM. Comments on “KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease”. Kidney Int 2013;84:622-623. 19. Wahlgren N, Ahmed N, D avalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-282. 20. Ovbiagele B, Smith EE, Schwamm LH, et al. Chronic kidney disease and bleeding complications after intravenous thrombolytic therapy for acute ischemic stroke. Circ Cardiovasc Qual Outcomes 2014;7:929-935.
21. Gensicke H, Zinkstok SM, Roos YB, et al. IV thrombolysis and renal function. Neurology 2013;81:1780-1788. 22. Naganuma M, Koga M, Shiokawa Y, et al. Reduced estimated glomerular filtration rate is associated with stroke outcome after intravenous rt-PA: The Stroke Acute Management with Urgent Risk-Factor Assessment and Improvement (SAMURAI) rt-PA Registry. Cerebrovasc Dis 2011;31:123-129. 23. Diprose WK, Sutherland LJ, Wang MTM, et al. Contrastassociated acute kidney injury in endovascular thrombectomy patients with and without baseline renal impairment. Stroke 2019;50:3527-3531. 24. Tsagalis G, Akrivos T, Alevizaki M, et al. Renal dysfunction in acute stroke: an independent predictor of longterm all combined vascular events and overall mortality. Nephrol Dial Transplant 2009;24:194-200. 25. Toyoda K, Ninomiya T. Stroke and cerebrovascular diseases in patients with chronic kidney disease. Lancet Neurol 2014;13:823-833. 26. Yahalom G, Schwartz R, Schwammenthal Y, et al. Chronic kidney disease and clinical outcome in patients with acute stroke. Cerebrovasc Dis 2011;31:271-277. 27. Holzmann MJ, Aastveit A, Hammar N, et al. Renal dysfunction increases the risk of ischemic and hemorrhagic stroke in the general population. Ann Med 2012;44:607-615. 28. Ovbiagele B. Chronic kidney disease and risk of death during hospitalization for stroke. J Neurol Sci 2011;301: 46-50. 29. Anavekar NS, McMurray JJV, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2014;351:1285-1295. 30. McCullough PA, Jurkovitz CT, Pergola PE, et al. Independent components of chronic kidney disease as a cardiovascular risk state: results from the Kidney Early Evaluation Program (KEEP). Arch Intern Med 2007;167:1122-1129. 31. Johnson DW, Armstrong K, Campbell SB, et al. Metabolic syndrome in severe chronic kidney disease: prevalence, predictors, prognostic significance and effects of risk factor modification. Nephrology 2007;12:391-398. 32. Murray AM. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Adv Chronic Kidney Dis 2008;15:123-132. 33. Diprose WK, Wang MTM, McFetridge A, et al. Glycated hemoglobin (HbA1c) and outcome following endovascular thrombectomy for ischemic stroke. J Neurointerv Surg 2020;12:30-32. 34. Diprose WK, Diprose JP, Wang MTM, et al. Automated measurement of cerebral atrophy and outcome in endovascular thrombectomy. Stroke 2019;50:3636-3638. 35. Ikram MA, Vernooij MW, Hofman A, et al. Kidney function is related to cerebral small vessel disease. Stroke 2008;39:55-61. 36. Tu HTH, Campbell BCV, Christensen S, et al. Worse stroke outcome in atrial fibrillation is explained by more severe hypoperfusion, infarct growth, and hemorrhagic transformation. Int J Stroke 2015;10:534-540. 37. Saeed F, Adil MM, Piracha BH, et al. Outcomes of endovascular versus intravenous thrombolytic treatment for acute ischemic stroke in dialysis patients. Int J Artif Organs 2014;37:727-733. 38. Chertow GM, Normand SLT. “Renalism”: inappropriately low rates of coronary angiography in elderly individuals with renal insufficiency. J Am Soc Nephrol 2004;15:2462-2468.
Chronic Kidney Disease and Outcome Following Endovascular Thrombectomy for Acute Ischemic Stroke Luke J. Sutherland, MBChB,* William K. Diprose, MBChB,†,‡ Michael T.M. Wang, MBChB,† and P. Alan Barber, MBChB, PhD, FRACP†,‡ Background and Objectives: Chronic kidney disease (CKD) is present in 20% to 35% of acute ischemic stroke patients and may increase the risk of poor functional outcome or death. We aimed to determine whether CKD was associated with worse outcome in stroke patients treated with endovascular thrombectomy (EVT). Design, Setting, Participants, and Measurements: Consecutive EVT patients were identified from a prospective registry and dichotomized into patients with and without CKD, defined as an eGFR of less than 60 mL/min/1.73m2. The primary outcome was 3-month mortality following EVT. Secondary outcomes included symptomatic intracerebral hemorrhage (defined by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study), early neurological recovery (defined as change in National Institutes of Health Stroke Scale [NIHSS] score of 8 at 24 hours or an NIHSS of 0-1 at 24 hours) and functional independence (defined as a modified Rankin Scale [mRS] score of 0, 1 or 2) at 3 months. Results: 378 EVT patients (223 men; mean § SD age 65 § 15 years) were included. The median (IQR) admission eGFR was 71 (58-89) mL/min/1.73 m2 and 117 (31%) patients had CKD. Multiple logistic regression adjusted for potential confounders demonstrated that CKD was a significant predictor of lower rates of functional independence (OR = .54, 95% CI, .31 to .90, P = .02), higher mRS scores (common OR = 1.78, 95% CI, 1.14 to 2.81, P = .01), and increased mortality (OR = 2.19, 95% CI, 1.16 to 4.12, P = .01). There was no association between CKD and early neurological recovery (OR = .92, 95% CI, .55 to 1.49, P = .71) or symptomatic intracerebral hemorrhage (OR = 1.18, 95% CI, .38 to 3.69, P = .77). Conclusions: CKD was a significant predictor of worse functional outcome and mortality in stroke patients treated with EVT. The presence of CKD should not preclude patients from proceeding to EVT, but may help with prognostication and improve shared decision-making between patients, families and physicians. Key Words: Chronic kidney disease—acute stroke—endovascular thrombectomy— nephrology © 2020 Elsevier Inc. All rights reserved.
Introduction From the *Department of Renal Medicine, Auckland City Hospital, Auckland, New Zealand; †Department of Medicine, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand; and ‡Department of Neurology, Auckland City Hospital, Auckland, New Zealand. Received November 13, 2019; revision received January 6, 2020; accepted January 11, 2020. Funding: The Neurological Foundation of New Zealand funds a Clinical Fellowship for Dr William Diprose. Address correspondence to P. Alan Barber, MBChB, PhD, FRACP, Department of Medicine, Faculty of Medical and Health Sciences, The University, of Auckland, Private Bag 92019, Auckland 1142. E-mail: [email protected]. 1052-3057/$ - see front matter © 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104665
Chronic kidney disease (CKD) increases the risk of stroke,1-6 and is present in 20% to 35% of acute ischemic stroke patients when defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2.7 Up to half of patients presenting with stroke with evidence of pre-existing CKD are unaware of this diagnosis.8 Maintenance hemodialysis patients also have a higher incidence of stroke, which is a major cause of death in these patients.9 Causes of increased stroke risk in CKD patients include vascular calcification, autonomic dysfunction, hyperhomocysteinemia, intradialytic volume shifts and vertebrobasilar steal from arteriovenous fistulae.10 There may also be lower use of pharmacotherapies, such as
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novel oral anticoagulants in CKD patients with atrial fibrillation.11 Patients treated with endovascular thrombectomy (EVT) are exposed to greater contrast volumes as a result of digital subtraction angiography than other stroke patients, and this may increase the risk of contrast-associated acute kidney injury, particularly in those with pre-existing CKD.12 In EVT patients, one study reported that CKD was associated with increased mortality but not with functional outcome or symptomatic intracerebral hemorrhage.13 We aimed to further define the relationship between CKD and outcome in stroke patients treated with EVT.
Methods Consecutive patients from a single-center prospective EVT registry between March 2011 and March 2019 were included if they had baseline creatinine measurements and follow-up data available. The study center is a tertiary hospital which provides EVT services to approximately 2.8 million people. The registry contains data regarding patient demographics, medical comorbidities, clinical and imaging features of the stroke, treatment details and patient outcomes. This study was approved by the institutional review board. All analyses were performed on deidentified data and the study was considered low risk, so informed consent was not required. Baseline and 24-hour stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) by the attending stroke team.14 The Alberta Stroke Program Early CT Score was used to assess the size of baseline infarct. 15 Successful recanalization was defined as a modified Thrombolysis in Cerebral Infarction (mTICI) score of 2b to 3.16 The Chronic Kidney Disease Epidemiology Collaboration equation was used to calculate estimated glomerular filtration rate (eGFR).17 Patients were dichotomized into patients with and without CKD, defined as an eGFR of less than 60 mL/min/1.73 m2.18 The primary outcome was 3-month mortality following EVT. Secondary outcomes included symptomatic intracerebral hemorrhage (defined by the Safe Implementation of Thrombolysis in StrokeMonitoring Study definition), early neurological recovery (defined as change in NIHSS of 8 at 24 hours or an NIHSS of 0-1 at 24 hours), functional independence at 3 months (defined as a modified Rankin Scale [mRS] score of 0, 1 or 2) and mRS at 3 months.19 Statistical analysis was performed using IBM SPSS Statistics version 25.0 (New York) and GraphPad Prism version 6.02 (California). Preliminary univariate logistic or ordinal regression and Fisher’s exact tests were used to identify potential clinical predictors of outcome measures. The relationship between CKD (defined as an eGFR < 60 mL/min/1.73 m2) and outcome measures was then assessed using multiple logistic or ordinal regression, incorporating relevant variables with P < .15 from the univariate analysis. The number of variables used in the
multivariable regression analysis was approximately limited to the number of adverse events divided by 10, to avoid overfitting. All tests were 2-tailed and P < .05 was considered statistically significant.
Results A total of 393 patients were screened for eligibility, 6 were excluded due to the absence of baseline creatinine measurements, and 9 were excluded due to the absence of follow-up data. There were 378 patients (223 men; mean § SD age 65 § 15 years, median [IQR] baseline NIHSS score of 17 [12-21]) included in the analysis (Table 1). 205 (54%) patients received intravenous therapy with alteplase. Successful recanalization (mTICI 2b-3) was achieved in 332 (88%) patients. The median (IQR) admission creatinine level was 88 (72-104) mmol/L and the median (IQR) eGFR was 71 (58-89) mL/min/1.73 m2. 117 (31%) patients had CKD. Patients with CKD were more likely to be older and have hypertension, hyperlipidemia, coronary artery disease and atrial fibrillation. Symptomatic intracerebral hemorrhage occurred in 16 (4%) patients. 182 (48%) patients exhibited early neurological improvement. At 3 months, 215 (57%) patients achieved functional independence and 58 (15%) had died. Unadjusted univariate and multivariable-adjusted odds ratios of outcome measures by admission renal function are presented in Table 2 and the distribution of 3-month mRS scores are illustrated in Figure 1. Multiple logistic regression adjusted for potential confounders demonstrated that CKD was associated with lower rates of functional independence (odds ratio [OR] = .54, 95% confidence interval [CI], .31 to .90, P = .02), higher mRS scores (common OR = 1.78, 95% CI, 1.14 to 2.81, P = .01), and increased mortality (OR = 2.19, 95% CI, 1.16 to 4.12, P = .01). There was no association between CKD and early neurological recovery (OR = .92, 95% CI, .55 to 1.49, P = .71) or sICH (OR = 1.18, 95% CI, .38 to 3.69, P = .77). Subgroup analysis conducted according to baseline eGFR stratification based on the stages of chronic kidney disease are presented in Table 3 and demonstrated similar trends, although increased mortality were limited to patients with a baseline eGFR of <30 mL/min/1.73 m2 (OR = 5.72, 95% CI, 1.41 to 21.34, P = .01).
Discussion Ischemic stroke patients treated with EVT who had CKD had lower rates of functional independence and were more likely to have died at 3 months. Patients with CKD were older and had higher rates of cardiovascular risk factors. These results are in contrast to an earlier study of stroke patients treated with EVT where an association was found between lower eGFR and higher rates of death but no association with functional independence or mRS scores.13 Neither study found an association between eGFR and symptomatic intracerebral hemorrhage. Similarly, a large
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Table 1. Baseline patient, procedure and outcome measures Parameters
All (n = 378)
eGFR < 60 (n = 117)
eGFR 60 (n = 261)
65 § 15 223 (59%)
74 § 11 70 (60%)
61 § 15 153 (59%)
74 (20%) 254 (67%) 175 (46%) 165 (44%) 66 (17%) 185 (49%)
28 (24%) 98 (84%) 67 (57%) 45 (38%) 30 (26%) 70 (60%)
46 (18%) 156 (60%) 108 (41%) 120 (46%) 36 (14%) 115 (44%)
0 (0-0) 154 § 28 17 (12-21) 9 (7-10) 309 (82%) 88 (72-104) 71 (58-89) 205 (54%)
0 (0-0) 157 § 27 18 (12-21) 9 (8-10) 99 (85%) 113 (101-129) 52 (41-56) 65 (56%)
0 (0-0) 153 § 28 17 (11-21) 9 (7-10) 210 (80%) 77 (66-89) 82 (70-94) 140 (54%)
332 (88%) 215 (165-310) 280 (225-385)
105 (90%) 215 (170-310) 275 (225-370)
227 (87%) 215 (165-315) 285 (225-390)
182 (48%) 14 (4%) 2 (1-4) 215 (57%) 58 (15%)
54 (46%) 5 (4%) 3 (1-5) 55 (47%) 27 (23%)
128 (49%) 9 (3%) 2 (1-3) 160 (61%) 31 (12%)
Age, yr, mean§SD Men, n (%) Risk factors Diabetes, n (%) Hypertension, n (%) Dyslipidemia, n (%) Smoking, n (%) Coronary artery disease, n (%) Atrial fibrillation, n (%) Baseline Prestroke mRS, median (IQR) Systolic blood pressure, mmHg, mean § SD NIHSS, median (IQR) ASPECTS, median (IQR) Anterior circulation occlusion site, n (%) Creatinine, mmol/L, median (IQR) eGFR, mL/min/1.73 m2, median (IQR) IV alteplase, n (%) Procedure mTICI 2b-3 recanalisation, n (%) LKN to puncture, mins, median (IQR) LKN to procedure completion, mins, median (IQR) Outcomes 24-hr early neurological improvement, n (%) sICH, n (%) 3-mon mRS, median (IQR) 3-mon functional independence, n (%) 3-mon mortality, n (%)
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; eGFR, estimated glomerular filtration rate; LKN, last known normal; mRS, modified Rankin Score; mTICI, modified Thrombolysis in Cerebral Infarction; NIHSS, National Institutes of Health Stroke Scale; and sICH, symptomatic intracerebral.
study of 44,410 stroke patients treated with intravenous thrombolysis, of whom 34% had an eGFR less than 60 mL/ min/1.73 m2, also found no association between CKD and symptomatic intracerebral hemorrhage.20 As well as an increased risk of ischemic stroke, lower eGFR is associated with increased risk of poor outcome, symptomatic intracerebral hemorrhage and death in stroke patients treated with intravenous thrombolysis (26%-32% of whom had an eGFR < 60 mL/min/1.73 m2).21,22 A recent analysis by our group found that CKD is associated with an increased risk of contrast-associated acute kidney injury (CA-AKI) in patients receiving EVT, and this in turn was associated with increased mortality (OR 4.68, 95% CI, 1.05-20.97; P = .04).23 The rate of CA-AKI was low, however, occurring in only 3.3% of patients. As a result, the confidence intervals for the association with increased mortality were unstable. CKD is also independently associated with worse functional outcomes after intracerebral
hemorrhage,24-28 and in patients with an acute coronary syndrome.29 How CKD confers increased risk of poor outcome in stroke patients treated with EVT is unclear. CKD patients are generally older and have other comorbidities such as hypertension, atrial fibrillation and ischemic heart disease, as seen in this study.22 Worsening eGFR may result in atherosclerosis, vascular calcification, anemia, oxidative stress, hyperhomocysteinemia and coagulation changes, increasing the risk of both stroke and worse outcomes following stroke.30,31 CKD results in accelerated chronic microvascular damage, which may impair the ability of the brain to recover from an acute ischemic insult, similar to that seen in EVT patients with cerebral atrophy or chronic hyperglycemia.32-34 Indeed, CKD patients have more extensive white matter lesions and reduced deep white matter volume.35 Finally, CKD patients with atrial fibrillation are less likely to be treated with novel oral
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Table 2. Logistic regression odds ratios of outcome measures by renal function Univariate logistic regression eGFR < 60
OR (95% CI)
24-hr early neurological improvement* sICHy 3-mon mRSz 3-mon functional independencex 3-mon mortality║
.89 (.58 to 1.38) 1.25 (.41 to 3.81) 1.76 (1.21 to 2.59) 0.56 (.36 to .87) 2.23 (1.26 to 3.94)
Multiple logistic regression
P value
OR (95% CI)
P value
.62 .69 .004 .009 .006
.92 (.55 to 1.49) 1.18 (.38 to 3.69) 1.78 (1.14 to 2.81) .54 (.31 to .90) 2.19 (1.16 to 4.12)
.71 .77 .01 .02 .01
Abbreviations: 95% CI, 95% confidence interval; mRS, modified Rankin Score; OR, odds ratio; and sICH, symptomatic intracerebral hemorrhage. *Multivariable analyses adjusted for age, diabetes, atrial fibrillation, baseline NIHSS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. † Multivariable analyses adjusted for diabetes, and coronary artery disease. ‡ Multivariable analyses adjusted for age, hypertension, diabetes, coronary artery disease, baseline mRS, baseline NIHSS, baseline ASPECTS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. § Multivariable analyses adjusted for age, hypertension, diabetes, coronary artery disease, baseline mRS, baseline NIHSS, baseline ASPECTS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. ║ Multivariable analyses adjusted for age, coronary artery disease, baseline NIHSS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation.
anticoagulants, and stroke patients with atrial fibrillation tend to have worse outcomes.36 Despite finding lower rates of functional independence and higher rates of mortality in these patients, we do not advocate withholding EVT in stroke patients with CKD. Previous studies have demonstrated the therapeutic benefit of EVT in CKD patients.37 In the cardiology literature, individuals with CKD have inappropriately low rates of coronary angiography, previously referred to as “renalism”.38 At our institution, low GFR is not an exclusion criterion for EVT and we could find no evidence that these patients were less likely to be offered EVT.
Limitations The data in this study are based on a modest sized cohort of consecutive, unselected patients presenting with stroke who proceeded to EVT. The single-center retrospective design has the potential to introduce selection bias and limit the generalizability of the findings. Most patients had been transferred for EVT from other hospitals and we were therefore limited to the data captured in our database. Despite the use of multivariable-adjusted logistic regression techniques, the potential for residual confounding from other unidentified factors cannot be
Figure 1. Distribution of 3-month mRS scores by renal function.
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Table 3. Logistic regression odds ratios of outcome measures by baseline eGFR stratification Univariate logistic regression OR (95% CI)
P value
Multiple logistic regression OR (95% CI)
P value
24-hr early neurological improvement* Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90
.91 (.55 to 1.52) .89 (.50 to 1.56) .54 (.17 to 1.75)
.91 .89 .54
.93 (.50-1.69) .92 (.45-1.94) .68 (.19 to 2.40)
.78 .86 .59
sICHy Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90
1.85 (.38-9.08) 1.76 (.31-9.83) 3.35 (.28-39.56)
.45 .52 .34
1.73 (.35-8.58) 1.61 (.28-9.03) 2.33 (.19-28.94)
.51 .60 .52
1.89 (1.20-2.99) 2.35 (1.42-3.90) 7.92 (2.82-22.19)
.006 .001 <.001
1.86 (1.12-3.22) 2.31 (1.26-4.19) 6.02 (1.92-18.87)
.02 .007 .002
.45 (.20 to .95) .40 (.16 to .86) .12 (.02 to .61)
.04 .02 .01
3-mon mRSz Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90 3-mon functional independencex Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90
.42 (.24 to .74) .36 (.19 to .66) .10 (.02 to .37)
.002 .001 .001
3-mon mortality║ Baseline eGFR, mL/min/1.73 m2 60-89 versus >90 30-59 versus >90 <30 versus >90
1.30 (.57 to 2.96) 2.28 (.98 to 5.27) 6.67 (1.89 to 23.57)
.53 .06 .003
1.35 (.55-3.34) 2.34 (.93 to 5.94) 5.72 (1.41 to 21.34)
.51 .08 .01
Abbreviations: 95% CI, 95% confidence interval; mRS, modified Rankin Score; OR, odds ratio; and sICH, symptomatic intracerebral hemorrhage. *Multivariable analyses adjusted for age, diabetes, atrial fibrillation, baseline NIHSS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. † Multivariable analyses adjusted for diabetes, and coronary artery disease. ‡ Multivariable analyses adjusted for age, hypertension, diabetes, coronary artery disease, baseline mRS, baseline NIHSS, baseline ASPECTS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. § Multivariable analyses adjusted for age, hypertension, diabetes, coronary artery disease, baseline mRS, baseline NIHSS, baseline ASPECTS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation. ║ Multivariable analyses adjusted for age, coronary artery disease, baseline NIHSS, anterior circulation occlusion site, intravenous alteplase therapy, last known normal to procedure completion, and mTICI 2b-3 recanalisation.
completely excluded. We were also not able to determine whether the baseline creatinine levels reflected pre-existing CKD or a concurrent acute kidney injury.
shared decision-making between patients, families and physicians.
Acknowledgments Conclusion This study has found an association between CKD and worse outcomes in acute ischemic stroke patients treated with EVT. The presence of CKD should not preclude patients from proceeding to EVT but considering baseline eGFR may improve prognostication and
The authors wish to acknowledge the The Neurological Foundation of New Zealand and The Julius Brendel Trust for their help in facilitating this research.
Conflict of Interest None.
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