American Journal of Kidney Diseases
Volume 54, Issue 3 , Pages 440-449 , September 2009

Homocysteine Lowering and Cognition in CKD: The Veterans Affairs Homocysteine Study

  • Christopher B. Brady, PhD

      Affiliations

    • Geriatric Research, Education, and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, MA
    • Department of Neurology, Boston University School of Medicine, Boston, MA
    • Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • Corresponding Author InformationAddress correspondence to Christopher B. Brady, PhD, GRECC(182), VA Boston Healthcare System, 150 S Huntington Ave, Boston, MA 02130
    • ,
  • J. Michael Gaziano, MD

      Affiliations

    • Geriatric Research, Education, and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, MA
    • Division of Aging, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, MA
    • ,
  • Roberta A. Cxypoliski, MSN

      Affiliations

    • Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, MA
    • ,
  • Peter D. Guarino, PhD

      Affiliations

    • Veterans Affairs Cooperative Studies Program Coordinating Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
    • ,
  • James S. Kaufman, MD

      Affiliations

    • Renal Section, Veterans Affairs Boston Healthcare System, Boston, MA
    • Renal Section, Boston University School of Medicine, Boston, MA
    • ,
  • Stuart R. Warren, PharmD

      Affiliations

    • Veterans Affairs Cooperative Studies Program, Clinical Research Pharmacy Coordinating Center, New Mexico Veterans Affairs Health Care System, Albuquerque, NM
    • College of Pharmacy, University of New Mexico, Albuquerque, NM
    • ,
  • Pamela Hartigan, PhD

      Affiliations

    • Veterans Affairs Cooperative Studies Program Coordinating Center, Veterans Affairs Connecticut Healthcare System, West Haven, CT
    • ,
  • David S. Goldfarb, MD

      Affiliations

    • Nephrology Section, New York Harbor Healthcare System, New York, NY
    • New York University School of Medicine, New York, NY
    • ,
  • Rex L. Jamison, MD

      Affiliations

    • Veterans Affairs Palo Alto Health Care System, Palo Alto, CA
    • Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA

Received 30 January 2009 ,Accepted 26 May 2009.

References 

  1. Kurella M, Chertow GM, Luan J, Yaffe K. Cognitive impairment in chronic kidney disease. J Am Geriatr Soc. 2004;52:1863–1869
  2. Kurella M, Yaffe K, Shlipak MG, Wenger NK, Chertow GM. Chronic kidney disease and cognitive impairment in menopausal women. Am J Kidney Dis. 2005;45:66–76
  3. Kurella Tamura M, Wadley V, Yaffe K, et al. Kidney function and cognitive impairment in US adults: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Am J Kidney Dis. 2008;52:227–234
  4. Madero M, Gul A, Sarnak MJ. Cognitive function in chronic kidney disease. Semin Dial. 2008;21:29–37
  5. Murray AM, Tupper DE, Knopman DS, et al. Cognitive impairment in hemodialysis patients is common. Neurology. 2006;67:216–223
  6. Pereira AA, Weiner DE, Scott T, Sarnak MJ. Cognitive function in dialysis patients. Am J Kidney Dis. 2005;45:448–462
  7. Seliger SL, Siscovick DS, Stehman-Breen CO, et al. Moderate renal impairment and risk of dementia among older adults: The Cardiovascular Health Cognition Study. J Am Soc Nephrol. 2004;15:1904–1911
  8. Weiner DE. The cognition-kidney disease connection: Lessons from population-based studies in the United States. Am J Kidney Dis. 2008;52:201–204
  9. Bostom AG, Shemin D, Verhoef P, et al. Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients (A prospective study). Arterioscler Thromb Vasc Biol. 1997;17:2554–2558
  10. Friedman AN, Bostom AG, Selhub J, Levey AS, Rosenberg IH. The kidney and homocysteine metabolism. J Am Soc Nephrol. 2001;12:2181–2189
  11. Jungers P, Massy ZA, Nguyen Khoa T, et al. Incidence and risk factors of atherosclerotic cardiovascular accidents in predialysis chronic renal failure patients: A prospective study. Nephrol Dial Transplant. 1997;12:2597–2602
  12. Dufouil C, Alperovitch A, Ducros V, Tzourio C. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol. 2003;53:214–221
  13. Elias MF, Sullivan LM, D'Agostino RB, et al. Homocysteine and cognitive performance in the Framingham offspring study: Age is important. Am J Epidemiol. 2005;162:644–653
  14. McCaddon A, Hudson P, Davies G, Hughes A, Williams JHH, Wilkinson C. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord. 2001;12:309–313
  15. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Hyperhomocysteinemia associated with poor recall in the Third National Health and Nutrition Examination Survey. Am J Clin Nutr. 2001;73:927–933
  16. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B-12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998;55:1449–1455
  17. Haan MN, Miller JW, Aiello AE, et al. Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: Results from the Sacramento Area Latino Study on Aging. Am J Clin Nutr. 2007;85:511–517
  18. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346:476–483
  19. Balk EM, Raman G, Tatsioni A, Chung M, Lau J, Rosenberg IH. Vitamin B6, B12, and folic acid supplementation and cognitive function: A systematic review of randomized trials. Arch Intern Med. 2007;167:21–30
  20. Jamison RL, Hartigan P, Gaziano JM, et al. Design and statistical issues in the Homocysteinemia in Kidney and End Stage Renal Disease (HOST) study. Clin Trials. 2004;1:451–460
  21. Jamison RL, Hartigan P, Kaufman JS, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: A randomized controlled trial. JAMA. 2007;298:1163–1170
  22. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41
  23. Griva K, Newman SP, Harrison MJ, et al. Acute neuropsychological changes in hemodialysis and peritoneal dialysis patients. Health Psychol. 2003;22:570–578
  24. Welsh KA, Breitner JC, Magruder-Habib KM. Detection of dementia in the elderly using telephone screening of cognitive status. Neuropsychiatry Neuropsychol Behav Neurol. 1993;6:103–110
  25. Crooks VC, Clark L, Petitti DB, Chui H, Chiu V. Validation of multi-stage telephone-based identification of cognitive impairment and dementia. BMC Neurol. 2005;5:8
  26. Gallo JJ, Breitner JCS. Alzheimer's disease in the NAS-NRC Registry of ageing twin veterans: IV. Performance characteristics of a two-stage telephone screening procedure for Alzheimer's dementia. Psychol Med. 1995;25:1211–1219
  27. Jarvenpaa T, Rinne JO, Raiha I, et al. Characteristics of two telephone screens for cognitive impairment. Dement Geriatr Cogn Disord. 2002;13:149–155
  28. Plassman BL, Newman TT, Welsh KA, et al. Properties of the telephone interview for cognitive status: Application in epidemiological and longitudinal studies. Neuropsychiatry Neuropsychol Behav Neurol. 1994;7:235–241
  29. Wechsler D. Wechsler Adult Intelligence Scale. (ed 3). San Antonio, CA: Psychological Corp; 1997;
  30. Lezak MD. Neuropsychological Assessment. New York, NY: Oxford University; 1995;
  31. Yesavage JA, Brink TL. Development and validation of a geriatric depression screening scale: A preliminary report. J Psychiatr Res. 1983;17:37–49
  32. Pliskin NH, Kiolbasa TA, Hart RP, Umans JG. Neuropsychological function in renal disease and its treatment. In:  Tarter RE,  Butters M editor. Medical Neuropsychology. (ed 2). New York, NY: Klumer Academic/Plenum; 2001;p. 107–126
  33. Montorio I, Izal M. The Geriatric Depression Scale: A review of its development and utility. Int Psychogeriatr. 1996;8:103–112
  34. Chelune GJ, Naugle RI, Lueders H, et al. Individual change after epilepsy surgery: Practice effects and base-rate information. Neuropsychology. 1993;7:41–52
  35. Collie A, Maruff P, Makdissi M, McStephen M, Darby DG, McCrory P. Statistical procedures for determining the extent of cognitive change following concussion. Br J Sports Med. 2004;38:273–278
  36. Hensel A, Angermeyer MC, Riedel-Heller SG. Measuring cognitive change in older adults: Reliable change indices for the Mini-Mental State Examination. J Neurol Neurosurg Psychiatry. 2007;78:1298–1303
  37. Aisen PS, Schneider LS, Sano M, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: A randomized controlled trial. JAMA. 2008;300:1774–1783
  38. Kang JH, Cook N, Manson J, Buring JE, Albert CM, Grodstein F. A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. Am J Clin Nutr. 2008;88:1602–1610
  39. McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006;354:2764–2772
  40. Stott DJ, MacIntosh G, Lowe GD, et al. Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. Am J Clin Nutr. 2005;82:1320–1326
  41. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004;291:565–575
  42. Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomised, double blind, controlled trial. Lancet. 2007;369:208–216
  43. Nulsen RS, Yaqoob MM, Mahon A, Stoby-Fields M, Kelly M, Varagunam M. Prevalence of cognitive impairment in patients attending pre-dialysis clinic. J Ren Care. 2008;34:121–126
  44. Kutlay S, Nergizoglu Gk, Duman N, et al. Recognition of neurocognitive dysfunction in chronic hemodialysis patients. Ren Fail. 2001;23:781–787
  45. Sehgal AR, Grey SF, DeOreo PB, Whitehouse PJ. Prevalence, recognition, and implications of mental impairment among hemodialysis patients. Am J Kidney Dis. 1997;30:41–49
  46. Tyrrell J, Paturel L, Cadec B, Capezzali E, Poussin G. Older patients undergoing dialysis treatment: Cognitive functioning, depressive mood and health-related quality of life. Aging Ment Health. 2005;9:374–379
  47. Monk RD, Bennett DA. Reno-cerebrovascular disease? (The incognito kidney in cognition and stroke). Neurology. 2006;67:196–198
  48. Elias MF, D'Agostino RB, Elias PK, Wolf PA. Neuropsychological test performance, cognitive functioning, blood pressure and age: The Framingham Heart Study. Exp Aging Res. 1995;21:369–391
  49. Elias MF, Elias PK, Robbins MA, Wolf PA, D'Agostino RB. Cardiovascular risk factors and cognitive functioning: An epidemiological perspective. In:  Waldstein SR,  Elias MF editor. Neuropsychology of Cardiovascular Disease. Mahwah, NJ: Erlbaum; 2001;p. 83–104
  50. Ryan CM. Diabetes-associated cognitive dysfunction. In:  Waldstein SR,  Elias MF editor. Neuropsychology of Cardiovascular Disease. Mahwah, NJ: Erlbaum; 2001;p. 61–82
  51. Waldstein SR, Katzel LI. Hypertension and cognitive function. In:  Waldstein SR,  Elias MF editor. Neuropsychology of Cardiovascular Disease. Mahwah, NJ: Erlbaum; 2001;p. 15–36
  52. Grodstein F, Kang JH, Glynn RJ, Cook NR, Gaziano JM. A randomized trial of beta carotene supplementation and cognitive function in men: The Physicians' Health Study II. Arch Intern Med. 2007;167:2184–2190
  53. Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E. Effect of postmenopausal hormone therapy on cognitive function: The Heart and Estrogen/progestin Replacement Study. Am J Med. 2002;113:543–548
  54. Kurella M, Chertow GM, Fried LF, et al. Chronic kidney disease and cognitive impairment in the elderly: The Health, Aging, and Body Composition Study. J Am Soc Nephrol. 2005;16:2127–2133
  55. Altmann P, Barnett ME, Finn WF. Cognitive function in stage 5 chronic kidney disease patients on hemodialysis: No adverse effects of lanthanum carbonate compared with standard phosphate-binder therapy. Kidney Int. 2007;71:252–259
  56. Colsher PL, Wallace RB. Longitudinal application of cognitive function measures in a defined population of community-dwelling elders. Ann Epidemiol. 1991;1:215–230
  57. Sliwinski M, Buschke H. Cross-sectional and longitudinal relationships among age, cognition, and processing speed. Psychol Aging. 1999;14:18–33
  58. Small BJ, Basun H, Backman L. Three-year changes in cognitive performance as a function of apolipoprotein E genotype: Evidence from very old adults without dementia. Psychol Aging. 1998;13:80–87
  59. Brady CB, Spiro A, McGlinchey-Berroth R, Milberg W, Gaziano JM. Stroke risk predicts verbal fluency decline in healthy older men: Evidence from the Normative Aging Study. J Gerontol Psychol Sci. 2001;56B:P340–P346
  60. B-Vitamin Treatment Trialists' Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: A review of the design and power of the large randomized trials. Am Heart J. 2006;151:282–287
  61. National Kidney Foundation. K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis. 2004;43(suppl 1):S14–S290

 This is a US Government Work. There are no restrictions on its use.

 Originally published online as doi: 10.1053/j.ajkd.2009.05.013 on July 24, 2009.

 Because an author of this manuscript is an editor for AJKD, the peer-review and decision-making processes were handled entirely by an Associate Editor (Michael Shlipak, MD, MPH, University of California, San Francisco) who served as Acting Editor-in-Chief. Details of the journal's procedures for potential editor conflicts are given in the Editorial Policies section of the AJKD website.

 Trial registration: www.clinicaltrials.gov; study number: NCT00032435.

PII: S0272-6386(09)00835-X

doi: 10.1053/j.ajkd.2009.05.013

American Journal of Kidney Diseases
Volume 54, Issue 3 , Pages 440-449 , September 2009

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