Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 2008;39:5-6
Published online before print November 29, 2007, doi: 10.1161/STROKEAHA.107.496000
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
39/1/5    most recent
STROKEAHA.107.496000v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Seliger, S. L.
Right arrow Articles by Longstreth, W.T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Seliger, S. L.
Right arrow Articles by Longstreth, W.T., Jr
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Kidney Diseases
Related Collections
Right arrow Epidemiology
Right arrow CT and MRI
Right arrow Other arteriosclerosis
Right arrowRelated Article

(Stroke. 2008;39:5.)
© 2008 American Heart Association, Inc.

Editorials

Lessons About Brain Vascular Disease From Another Pulsating Organ, the Kidney

Stephen L. Seliger, MD, MS W.T. Longstreth, Jr, MD, MPH

From the Division of Nephrology (S.L.S.), Department of Medicine, University of Maryland, Baltimore, Md; and Departments of Neurology and Epidemiology (W.T.L.), University of Washington, Seattle, Wash.

Correspondence to W.T. Longstreth, Jr, Department of Neurology, Box 359775, Harborview Medical Center, 325 Ninth Ave, Seattle, WA 98104-2420. E-mail wl{at}u.washington.edu


Key Words: epidemiology • lacunar infarcts • leukoaraiosis • MRI • renal disease

See related article, pages 55–61.

Because of similarities in the vascular supply to kidney and brain, information about vascular disease in one organ may inform us about vascular disease in the other, and such knowledge may shed light on ways to treat or prevent these diseases. Unlike most organs, both kidney and brain are low resistance end-organs and are exposed to high-volume blood flow throughout the cardiac cycle, explaining their pulsating nature.1 For the kidney, impairments from vascular disease manifest as problems with glomerular filtration, detected clinically by biochemical makers such as serum creatinine, urinary albumin, and serum cystatin C. For the brain, impairments manifest with overt focal neurological deficits, such as with stroke or transient ischemic attack, or as covert global deficits affecting cognition, mobility and mood, such as has been suggested with small-vessel disease. In humans, investigation of brain vascular disease and how it causes impairment of brain function often entails looking at the structure of the brain with MRI for infarctions, white matter lesions, and volumes of brain, ventricles and sulci. Given the difficulty in getting tissue, exploration of cause usually does not include microscopic examination of brain tissue, although microinfarcts inapparent on MRI can be identified.2 For investigation of vascular disease in the kidney, structural changes detectable on imaging are limited primarily to decrements in kidney size due to chronic fibrosis and atrophy. On the other hand, tissue is more readily available than from the brain and shows vascular changes analogous to those described in the brain, including arteriolar intima-media thickening and hyalinosis.3,4

In support of the idea that one organ may tell us about the other, Ikram and colleagues describe cross-sectional associations of renal function and MRI-defined findings of brain vascular disease in a population-based cohort of 484 older adults with a mean age of 73 years from the Rotterdam Scan Study.5 Mean estimated glomerular filtration rate (eGFR) based on serum creatinine and other variables was 58 mL/min per 1.73 m2 indicating that a substantial proportion had impaired renal function, defined by eGFR being <60 mL/min per 1.73 m2. Lower renal function was correlated with a smaller volume of normal white matter, especially deep rather than lobar, and a larger volume of white matter lesions, estimated using an automated volumetric technique. In contrast, eGFR was not associated with MRI-defined infarct after adjustment for vascular risk factors.

Others have also described associations between vascular disease of the kidney and brain. At one extreme, patients with end-stage renal disease, defined by an eGFR <15 mL/min per 1.73 m2 or kidney replacement therapy, are at 3 to 9 times greater risk for stroke compared with the general population, even after accounting for age, gender and race.6 Among patients with end-stage renal disease without a history of stroke or transient ischemic attacks, about 50% have MRI-defined infarcts, and those harboring covert brain infarcts are at significantly increased risk of future overt vascular events compared with those whose MRI are free of infarcts.7,8 An excess of white matter lesions have also been found on the MRI of patients with end-stage renal disease.9,10 In individuals with mild to moderate chronic kidney disease not requiring dialysis, 30% to 60% excess risk of clinically overt stroke has also been reported, even after adjustment for common stroke risk factors. This association has been demonstrated in hypertensive patients, as well as in population-based cohorts.11–13 Risks of covert MRI-defined infarcts and white matter lesions are also increased.14–16 In the Cardiovascular Health Study of community-dwelling adults age 65 years and older, prevalence of MRI-defined infarcts was higher in those with impaired kidney function compared with those without, as measured by cystatin C but not as measured by creatinine.15 Such observations raise questions about whether cystatin C may be superior to creatinine as a measure of impaired kidney function that relates to risk of future vascular events.13 As would be predicted by these studies, associations between measures of kidney function and brain function, namely dementia and cognitive decline, have also been described.17,18

Possibly some shared risk factor such as diabetes or hypertension could lead to a similar vascular injury in both kidney and brain and explain these associations. Diabetes seems unlikely to have an important role given how few of the participants in the population-based studies have this condition, specifically <5% in the Rotterdam Scan study described here.5 Hypertension is the obvious choice but in most studies adjustment in statistical models for hypertension does not eliminate the association. Nevertheless, differences in duration and long-term control of hypertension are usually not considered in large cohort studies of vascular disease. Even if one accounted for long-term control of peripheral blood pressure, differences in some other aspect of blood pressure may exist, such as central aortic pressure or diurnal variations in blood pressure. Impaired renal function is associated with the loss of the normal nocturnal drop in blood pressure, so called "dipping", and diurnal variations in blood pressure have been associated with MRI-defined small-vessel disease.19,20 Also unknown are genetic factors that may make kidney and brain more susceptible or resistant to common vascular risk factors.

Rather than simply shared insults, perhaps impairments of kidney function lead to brain injury directly or indirectly by modifying the effects of some risk factor. For example, with impaired kidney function, levels of endogenous inhibitors of nitric oxide synthase are increased, and metabolites of nitric oxide are decreased.21 Nitric oxide regulates microcirculation and blood-brain barrier,9,22 both of which have been implicated in the development of white matter lesions and other manifestations of brain small-vessel disease.23 Endothelial dysfunction of the conduit arteries—in part as a result of this reduced nitric oxide availability—is also common in kidney disease24 and might plausibly contribute to small-vessel disease of the brain.25 A similar argument could be made for homocysteine and inflammation, which increase with impaired kidney function and have been associated with MRI-defined small-vessel disease. Nonetheless, the associations in the current Rotterdam Scan Study persisted after adjustment for levels of homocysteine and C-reactive protein,5 suggesting other as yet unidentified factors have more important mediating effects.

The accumulating evidence, to which the work of Ikram and colleagues5 can now be added, indicates a link between vascular disease of the kidney and brain. Challenges remain in deciding what are the most appropriate measures of impaired function in these organs. Whether kidney and brain share unique susceptibilities to vascular injury, especially from central aortic pressure,1 or whether impaired kidney function itself contributes to impaired brain function requires clarification of molecular and genetic mechanisms. Understanding the interplay of vascular disease in these 2 organs holds the promise of finding novel means to reduce the risk of impaired function, especially in the brain. The path to this understanding begins with the type of study reported by Ikram and colleagues and requires continued collaboration of nephrologists and neurologists.

Acknowledgments

Disclosures

Both authors are coinvestigators in the Cardiovascular Health Study.

Footnotes

The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension. 2005; 46: 200–204.[Abstract/Free Full Text]
  2. White L, Petrovitch H, Hardman J, Nelson J, Davis DG, Ross GW, Masaki K, Launer L, Markesbery WR. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci. 2002; 977: 9–23.[Abstract/Free Full Text]
  3. Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R, Kalaria RN, Forster G, Esteves F, Wharton SB, Shaw PJ, O’Brien JT, Ince PG. White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 2006; 37: 1391–1398.[Abstract/Free Full Text]
  4. Fogo A, Breyer JA, Smith MC, Cleveland WH, Agodoa L, Kirk KA, Glassock R; AASK Pilot Study Investigators. Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. Kidney Int. 1997; 51: 244–252.[Medline] [Order article via Infotrieve]
  5. Ikram MA, Vernooij MW, Hofman A, Niessen WJ, van der Lugt A, Breteler MMB. Kidney function is related to cerebral small vessel disease. Stroke. 20078; 39: 55–61.[CrossRef]
  6. Seliger SL, Gillen DL, Longstreth WT Jr, Kestenbaum B, Stehman-Breen CO. Elevated risk of stroke among patients with end-stage renal disease. Kidney Int. 2003; 64: 603–609.[CrossRef][Medline] [Order article via Infotrieve]
  7. Nakatani T, Naganuma T, Uchida J, Masuda C, Wada S, Sugimura T, Sugimura K. Silent cerebral infarction in hemodialysis patients. Am J Nephrol. 2003; 23: 86–90.[CrossRef][Medline] [Order article via Infotrieve]
  8. Naganuma T, Uchida J, Tsuchida K, Takemoto Y, Tatsumi S, Sugimura K, Nakatani T. Silent cerebral infarction predicts vascular events in hemodialysis patients. Kidney Int. 2005; 67: 2434–2439.[CrossRef][Medline] [Order article via Infotrieve]
  9. Fazekas G, Fazekas F, Schmidt R, Kapeller P, Offenbacher H, Krejs GJ. Brain MRI findings and cognitive impairment in patients undergoing chronic hemodialysis treatment. J Neurol Sci. 1995; 134: 83–88.[CrossRef][Medline] [Order article via Infotrieve]
  10. Martinez-Vea A, Salvado E, Bardaji A, Gutierrez C, Ramos A, Garcia C, Compte T, Peralta C, Broch M, Pastor R, Angelet P, Marcas L, Sauri A, Oliver JA. Silent cerebral white matter lesions and their relationship with vascular risk factors in middle-aged predialysis patients with CKD. Am J Kidney Dis. 2006; 47: 241–250.[CrossRef][Medline] [Order article via Infotrieve]
  11. Wannamethee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease: a possible marker for increased risk of stroke. Stroke. 1997; 28: 557–563.[Abstract/Free Full Text]
  12. Ruilope LM, Salvetti A, Jamerson K, Hansson L, Warnold I, Wedel H, Zanchetti A. Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol. 2001; 12: 218–225.[Abstract/Free Full Text]
  13. Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, Siscovick DS, Stehman-Breen C. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med. 2005; 352: 2049–2060.[Abstract/Free Full Text]
  14. Kobayashi S, Ikeda T, Moriya H, Ohtake T, Kumagai H. Asymptomatic cerebral lacunae in patients with chronic kidney disease. Am J Kidney Dis. 2004; 44: 35–41.[CrossRef][Medline] [Order article via Infotrieve]
  15. Seliger SL, Longstreth WT Jr, Katz R, Manolio T, Fried LF, Shlipak M, Stehman-Breen CO, Newman A, Sarnak M, Gillen DL, Bleyer A, Siscovick DS. Cystatin C and subclinical brain infarction. J Am Soc Nephrol. 2005; 16: 3721–3727.[Abstract/Free Full Text]
  16. Khatri M, Wright CB, Nickolas TL, Yoshita M, Li L, Kranwinkel G, DeCarli C, Sacco RL. Chronic kidney disease is associated with white matter hyperintensity volume: the Northern Manhattan Study (abstract). Stroke. 2007; 38: 539.
  17. Seliger SL, Siscovick DS, Stehman-Breen CO, Gillen DL, Fitzpatrick A, Bleyer A, Kuller LH. Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study. J Am Soc Nephrol. 2004; 15: 1904–1911.[Abstract/Free Full Text]
  18. Khatri M, Nickolas T, Huamg L, Santiago M, Sacco R, Wright C. Chronic kidney disease is associated with cognitive decline: the Northern Manhattan Study (abstract). Neurology. 2007; 68 (suppl 1): A173–174.[CrossRef]
  19. Yamamoto Y, Akiguchi I, Oiwa K, Hayashi M, Ohara T, Ozasa K. The relationship between 24-hour blood pressure readings, subcortical ischemic lesions and vascular dementia. Cerebrovasc Dis. 2005; 19: 302–308.[CrossRef][Medline] [Order article via Infotrieve]
  20. Schwartz GL, Bailey KR, Mosley T, Knopman DS, Jack CR Jr, Canzanello VJ, Turner ST. Association of ambulatory blood pressure with ischemic brain injury. Hypertension. 2007; 49: 1228–1234.[Abstract/Free Full Text]
  21. Kielstein JT, Boger RH, Bode-Boger SM, Frolich JC, Haller H, Ritz E, Fliser D. Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease. J Am Soc Nephrol. 2002; 13: 170–176.[Abstract/Free Full Text]
  22. Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci. 2004; 5: 347–360.[CrossRef][Medline] [Order article via Infotrieve]
  23. Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003; 34: 806–812.[Abstract/Free Full Text]
  24. Yilmaz MI, Saglam M, Caglar K, Cakir E, Sonmez A, Ozgurtas T, Aydin A, Eyileten T, Ozcan O, Acikel C, Tasar M, Genctoy G, Erbil K, Vural A, Zoccali C. The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine. Am J Kidney Dis. 2006; 47: 42–50.[CrossRef][Medline] [Order article via Infotrieve]
  25. Hoth KF, Tate DF, Poppas A, Forman DE, Gunstad J, Moser DJ, Paul RH, Jefferson AL, Haley AP, Cohen RA. Endothelial function and white matter hyperintensities in older adults with cardiovascular disease. Stroke. 2007; 38: 308–312.[Abstract/Free Full Text]

Related Article:

Kidney Function Is Related to Cerebral Small Vessel Disease
M. Arfan Ikram, Meike W. Vernooij, Albert Hofman, Wiro J. Niessen, Aad van der Lugt, and Monique M.B. Breteler
Stroke 2008 39: 55-61. [Abstract] [Full Text] [PDF]




This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
39/1/5    most recent
STROKEAHA.107.496000v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Seliger, S. L.
Right arrow Articles by Longstreth, W.T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Seliger, S. L.
Right arrow Articles by Longstreth, W.T., Jr
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Kidney Diseases
Related Collections
Right arrow Epidemiology
Right arrow CT and MRI
Right arrow Other arteriosclerosis
Right arrowRelated Article

Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2008 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.