New Insights Into Stroke in Chronic Kidney Disease

  • Sami L. Khella
    Address correspondence to Sami L. Khella, MD, Department of Neurology, MOB, Suite 320, Penn Presbyterian Medical Center, 39th and Market Street, Philadelphia, PA 19104.
    Department of Neurology, University of Pennsylvania School of Medicine; Philadelphia, PA
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      Patients with chronic kidney disease (CKD) are predisposed to stroke, especially as the estimated glomerular filtration rate decreases. This update reviews the pathologic mechanisms particular to this stroke population. The treatment for primary and secondary prevention of stroke is reviewed with respect to antiplatelet agents, anticoagulants, surgery, and carotid stenting. The control of chronic hypertension is particularly important in reducing stroke risk in CKD. In patients with prior stroke from atherosclerosis, antiplatelet agents are most beneficial in reducing secondary stroke risk. Those with atrial fibrillation and CKD may benefit from warfarin anticoagulation. Statins in CKD for stroke reduction in diabetics receiving dialysis are not useful, and the data are pending for their use in stroke reduction in the general CKD population. In carefully selected cases, carotid endarterectomy can be a treatment. The data on carotid stenting are conflicting.

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        • Khella S.L.
        • Bleicher M.B.
        Stroke and its prevention in chronic kidney disease.
        Clin J Am Soc Nephrol. 2007; 2: 1343-1351
        • Bos M.J.
        • Koudstaal P.J.
        • Hofman A.
        • et al.
        Decreased glomerular filtration rate is a risk factor for hemorrhagic but not for ischemic stroke. The Rotterdam Study.
        Stroke. 2007; 38: 3127
        • 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
        • Weiner D.E.
        • Tighiouart H.
        • Amin M.G.
        • et al.
        Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: A pooled analysis of community-based studies.
        J Am Soc Nephrol. 2004; 15: 1307-1315
        • Anavekar N.S.
        • McMurray J.J.
        • Velazquez E.J.
        • et al.
        Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.
        N Engl J Med. 2004; 351: 1285-1295
        • McCullough P.A.
        • Li S.
        • Jurkovitz C.T.
        • et al.
        Chronic kidney disease and cardiovascular disease in volunteer and randomly selected populations: KEEP and NHANES.
        Am J Kidney Dis. 2008; 51 (B68–B68)
        • Weiner D.E.
        • Tighiouart H.
        • Stark P.C.
        Kidney disease is a risk factor for recurrent cardiovascular disease and mortality.
        Am J Kidney Dis. 2004; 44: 198-206
        • Abramson J.L.
        • Jurkvitz C.T.
        • Vaccarino V.
        • et al.
        Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: The ARIC study.
        Kidney Int. 2003; 64: 610-615
        • Nakayama M.
        • Metoki H.
        • Terawak H.
        • et al.
        Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population—The Ohasama study.
        Nephrol Dial Transplant. 2007; 22: 1910-1915
        • van der Sande F.M.
        • Hermans M.M.
        • Leunissen K.M.
        • et al.
        Noncardiac consequences of hypertension in hemodialysis patients.
        Semin Dial. 2004; 17: 304-306
        • Aull-Watschinger S.
        • Konstantin H.
        • Demetriou D.
        • et al.
        Pre-transplant predictors of cerebrovascular events after kidney transplantation.
        Nephrol Dial Transplant. 2007; 23: 1429-1435
        • Oliveras A.
        • Roquer J.
        • Puig J.M.
        • et al.
        Stroke in renal transplant recipients: Epidemiology, predictive risk factors and outcome.
        Clin Transplant. 2003; 17: 1-8
        • Caplan L.R.
        • Gorelick P.
        • Hier D.
        Race, sex, and occlusive cerebrovascular disease: A review.
        Stroke. 1986; 17: 648-655
        • Mohr J.P.
        • Caplan L.R.
        • Melski J.W.
        The Harvard Cooperative Stroke Registry: A prospective registry.
        Neurology. 1978; 28: 754-762
        • Seliger S.L.
        • Gillen D.L.
        • Longstreth Jr., W.T.
        • et al.
        Elevated risk of stroke among patients with end-stage renal disease.
        Kidney Int. 2003; 64: 603-609
        • 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
        • Savitz S.I.
        • Caplan L.R.
        Vertebrobasilar disease.
        N Engl J Med. 2005; 352: 2618-2626
      1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
        JAMA. 2002; 288: 2981-2987
        • Psaty B.M.
        • Smith N.L.
        • Siscovick D.S.
        • et al.
        Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis.
        JAMA. 1997; 277: 739-745
      2. The Heart Outcomes Prevention Evaluation Study Investigators: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
        N Engl J Med. 2000; 342: 145-153
        • Hansson L.
        • Lithell H.
        • Skoog I.
        • et al.
        Study on cognition and prognosis in the elderly (SCOPE): Principal results of a randomized double-blind intervention trial.
        Blood Press. 1999; 8: 177-183
        • Bosch J.
        • Yusuf S.
        • Pogue J.
        • et al.
        Use of ramipril in preventing stroke: Double blind randomised trial.
        BMJ. 2002; 324: 699-702
        • Lithell H.
        • Hansson L.
        • Skoog I.
        • et al.
        The Study on Cognition and Prognosis in the Elderly (SCOPE): Principal results of a randomized double-blind intervention trial.
        J Hypertens. 2003; 21: 875-886
        • Staessen J.A.
        • Wang J.G.
        Birkenhäger WH: Outcome beyond blood pressure control?.
        Eur Heart J. 2003; 24: 504-514
        • Weiner D.E.
        • Tighiouart H.
        • Levey A.S.
        • et al.
        Lowest systolic blood pressure is associated with stroke in stages 3 to 4 chronic kidney disease.
        J Am Soc Nephrol. 2007; 18: 960-966
        • Ninomiya T.
        • Perkovic V.
        • Gallagher M.
        • et al.
        Lower blood pressure and risk of recurrent stroke in patients with chronic kidney disease: PROGRESS trial.
        Kidney Int. 2008; 73: 963-970
      3. Committee Progress Management: PROGRESS–Perindopril Protection Against Recurrent Stroke Study: Characteristics of the study population at baseline.
        J Hypertens. 1999; 17 (1647–1645)
        • Steinmetz O.M.
        • Panzer U.
        • Stahl R.A.K.
        • et al.
        Statin therapy in patients with chronic kidney disease: To use or not to use.
        Eur J Clin Invest. 2006; 36: 519-527
        • Bianchi S.
        • Bigazzi R.
        • Caiazza A.
        • et al.
        A controlled prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease.
        Am J Kidney Dis. 2003; 41: 565-570
        • Wanner C.
        • Krane V.
        • März W.
        • et al.
        Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.
        N Engl J Med. 2005; 353: 238-248
        • Fellstrom B.
        • Holdaas H.
        • Jardine A.G.
        • et al.
        Effect of rosuvastatin on outcomes in chronic haemodialysis patients: Baseline data from the AURORA Study.
        Kidney Blood Press Res. 2007; 30: 314-322
        • Baigent C.
        • Landray M.
        • Leaper C.
        • et al.
        First United Kingdom Heart and Renal Protection (UK-HARP-I) Study: Biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease.
        Am J Kidney Dis. 2005; 45: 473-484
        • Baigent C.
        • Landry M.
        Study of Heart and Renal Protection (SHARP).
        Kidney Int. 2003; 84: S207-S210
      4. The Canadian Cooperative Study Group: A randomized trial of aspirin and sulfinpyrazone in threatened stroke.
        N Engl J Med. 1978; 299: 53-59
        • Bousser M.G.
        • Eschwege E.
        • Haguenau M.
        • et al.
        “AICLA” controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia.
        Stroke. 1983; 14: 4-14
        • Farrell B.
        • Godwin J.
        • Richards S.
        • et al.
        The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: Final results.
        J Neurol Neurosurg Psychiatry. 1991; 54: 1044-1054
      5. The SALT Collaborative Group: Swedish aspirin low-dose trial (SALT) of 75 mg of aspirin as secondary prophylaxis after cerebral vascular ischemic events.
        Lancet. 1991; 338: 1345-1349
        • Van Gijn J.
        • Algra A.
        Secondary stroke prevention with antithrombotic drugs: What to do next?.
        Cerebrovasc Dis. 1997; 7: 30-32
        • Algra A.
        • van Gijn J.
        Cumulative meta-analysis of aspirin efficacy after cerebral ischaemia of arterial origin.
        J Neurol Neurosurg Psychiatry. 1996; 66: 197-199
      6. Collaboration Antithrombotic Trialists: Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
        BMJ. 2000; 324: 71-86
        • Gorelick P.
        • Weisman S.
        Risk of hemorrhagic stroke with aspirin use. An update.
        Stroke. 2005; 36: 1801-1807
      7. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.
        Lancet. 1996; 348: 1329-1339
        • Diener H.C.
        • Cunha L.
        • Forbes C.
        • et al.
        European Stroke Prevention Study: 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.
        J Neurol Sci. 1996; 143: 1-13
        • Kaufman J.S.
        • O'Connor T.Z.
        • Zhang J.H.
        • et al.
        Randomized controlled trial of clopidogrel plus aspirin to prevent hemodialysis access graft thrombosis.
        J Am Soc Nephrol. 2003; 14: 2313-2321
        • Best P.J.M.
        • Steinhubl S.R.
        • Berger P.B.
        • et al.
        The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: Results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.
        Am Heart J. 2008; 155: 687-693
        • Diener H.C.
        • Cunha L.
        • Forbes C.
        • et al.
        European stroke prevention study: 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.
        J Neurol Sci. 1996; 143: 1-13
        • Gent M.
        • Blakely J.A.
        • Easton J.D.
        • et al.
        The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke.
        Lancet. 1989; 1: 1215-1220
        • Rothwell P.M.
        • Eliasziw M.
        • Gutnikov S.A.
        • et al.
        Carotid Endarterectomy Trialists' Collaboration. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis.
        Lancet. 2003; 361: 107-116
        • Barnett H.J.
        • Taylor D.W.
        • Eliasziw M.
        • et al.
        Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators.
        N Engl J Med. 1998; 339: 1415-1425
        • Tarakji A.
        • McConaughy A.
        • Nicholas G.G.
        The risk of carotid endarterectomy in patients with chronic renal insufficiency, current surgery.
        J Vasc Surg. 2006; 63: 326-329
        • Ascher E.
        • Marks N.A.
        • Schulzer R.W.
        • et al.
        Carotid endarterectomy in patients with chronic renal insufficiency: A recent series of 184 cases.
        J Vasc Surg. 2005; 41: 24-29
        • Stoner M.C.
        • Abbott W.M.
        • Wong D.R.
        • et al.
        Defining the high-risk patient for carotid endarterectomy: An analysis of the prospective National Surgical Quality Improvement Program database.
        J Vasc Surg. 2006; 43: 285-295
        • Mathew A.
        • Devereaux P.J.
        • O'Hare A.
        • et al.
        Chronic kidney disease and postoperative mortality: A systematic review and meta-analysis.
        Kidney Int. 2008; 73: 1069-1081
        • Debing E.
        • Van den Brande P.
        Chronic renal insufficiency and risk of early mortality in patients undergoing carotid endarterectomy.
        Ann Vasc Surg. 2006; 20: 609-613
        • Mas J.L.
        • Chatellier G.
        • Beyssen B.
        • et al.
        Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
        N Engl J Med. 2006; 355: 1660-1671
        • Yadav J.S.
        • Wholey M.H.
        • Kuntz R.E.
        • et al.
        Protected carotid-artery stenting versus endarterectomy in high-risk patients.
        N Engl J Med. 2004; 351: 1493-1501
        • Bogousslavsky J.
        • Cachin C.
        • Regli F.
        • et al.
        Cardiac sources of embolism and cerebral infarction-clinical consequences and vascular concomitants: The Lausanne Stroke Registry.
        Neurology. 1991; 41: 855-859
        • Kittner S.J.
        • Sharkness C.M.
        • Price T.R.
        • et al.
        Infarcts with a cardiac source of embolism in NINCDS Stroke Data Bank: historical features.
        Neurology. 1990; 40: 281-284
        • Vázquez E.
        • Sánchez-Perales C.
        • Borrego F.
        • et al.
        Influence of atrial fibrillation on the morbido-mortality of patients on hemodialysis.
        Am Heart J. 2000; 140: 886-890
        • Genovesi S.
        • Pogliani D.
        • Faini A.
        • et al.
        Prevalence of atrial fibrillation and associated factors in a population of long-term hemodialysis patients.
        Am J Kidney Dis. 2005; 46: 897-902
        • Weisholzer M.
        • Harm F.
        • Tomasec G.
        • et al.
        Incidence of stroke among chronic hemodialysis patients with nonrheumatic atrial fibrillation.
        Am J Nephrol. 2001; 21: 35-39
        • Harnett J.D.
        • Foley R.N.
        • Kent G.M.
        • et al.
        Congestive heart failure in dialysis patients: Prevalence, incidence, prognosis, and risk factors.
        Kidney Int. 1993; 47: 884-890
        • Fabbian F.
        • Catalano C.
        • Lambertini D.
        • et al.
        Clinical characteristics associated to atrial fibrillation in chronic hemodialysis patients.
        Clin Nephrol. 2000; 54: 234-239
        • Vasquez E.
        • Sanchez-Perales C.
        • Lozano C.
        • et al.
        Comparison of prognostic value of atrial fibrillation versus sinus rhythm in patients on long-term hemodialysis.
        Am J Cardiol. 2003; 92: 868-871
        • To A.C.
        • Yehia M.
        • Collins J.F.
        Atrial fibrillation in haemodialysis patients: Do the guidelines for anticoagulation apply?.
        Nephrology. 2007; 12: 441-447
      8. Stroke prevention in atrial fibrillation study. Final results.
        Circulation. 1991; 84: 527-539
      9. Stroke Prevention in Atrial Fibrillation Investigators: Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation. Stroke Prevention in Atrial Fibrillation III randomized clinical trial.
        Lancet. 1996; 348: 633-638
      10. European Atrial Fibrillation Trial (EAFT) Study Group: Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
        Lancet. 1993; 342: 1255-1262
      11. Stroke Prevention in Atrial Fibrillation Investigators: Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study.
        Lancet. 1999; 343: 687-691
      12. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators: The Boston Area Anticoagulation Trial for Atrial Fibrillation: The effect of low-dose warfarin on the risk of stoke in patients with nonrheumatic atrial fibrillation.
        N Engl J Med. 1990; 323: 1505-1511
        • Koos R.
        • Mahnken A.H.
        • Mühlenbruch G.
        • et al.
        Relation of oral antiboagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography.
        Am J Cardiol. 2005; 96: 747-749
        • Coates T.
        • Kirkland G.S.
        • Dymock R.B.
        • et al.
        Cutaneous necrosis from calcific uremic arteriolopathy.
        Am J Kidney Dis. 1998; 32: 384-391
        • Bazari H.
        • Jaff M.R.
        • Mannstadt M.
        • et al.
        Case 7-2007—A 59-year-old woman with diabetic renal disease and nonhealing skin ulcers.
        N Engl J Med. 2007; 356: 1049-1057