Albuminuria and Cerebral Small Vessel Disease: A Systematic
Review and Meta-Analysis
Marios K. Georgakis, MD, MSc,* Despoina Chatzopoulou, MD,* Georgios Tsivgoulis, MD, MSc,
and Eleni Th. Petridou, MD, MPH, PhD*
OBJECTIVES: To determine whether albuminuria, a mar-
ker of systemic endothelial dysfunction, is associated with
cerebral small vessel disease (SVD).
DESIGN: Systematic review following the Meta-analyses
Of Observational Studies in Epidemiology guidelines; inde-
pendent reviewers searched Pubmed/Medline and Scopus,
data were extracted, studies were evaluated on quality,
and random-effects models were implemented for meta-
SETTING: Observational studies quantifying an associa-
tion between albuminuria and cerebral SVD.
MEASUREMENTS: Magnetic resonance imaging–deﬁned
markers of cerebral SVD; white matter hyperintensities
(WMHs), lacunar infarcts (LIs), cerebral microbleeds
(CMBs), and enlarged perivascular spaces (EPVSs).
RESULTS: Of 31 eligible studies comprising 23,056 par-
ticipants identiﬁed, 27 were included in quantitative syn-
thesis. Most of the studies were cross-sectional and of
varying quality. On meta-analysis, albuminuria was associ-
ated with greater risk of WMHs (odds ratio (OR) = 1.70,
95% conﬁdence interval (CI) = 1.43–2.01; 13,548 sub-
jects, 2,665 cases; I
= 44%), LIs (OR = 1.86, 95%
CI = 1.49–2.31; 12,857 subjects, 998 cases; I
CMBs (OR = 1.78, 95% CI = 1.30–2.43; 7,645 subjects;
748 cases; I
= 39%), and EPVSs in the basal ganglia
(OR = 1.78, 95% CI = 1.02–3.09; 1,388 subjects, 399
= 37%) and centrum semiovale (OR = 3.27, 95%
CI = 1.49–7.20; 1,146 subjects, 460 cases; I
= 66%). Sen-
sitivity analyses for high-quality and general population
studies, but also studies controlling for cardiovascular dis-
ease risk factors and renal function, conﬁrmed the ﬁndings
and resolved the moderate heterogeneity and publication
bias that were evident in the overall analyses.
CONCLUSION: Albuminuria is independently associated
with cerebral SVD, indicating shared microvascular pathol-
ogy in the kidney and the brain. The results suggest that
peripheral systemic microvascular disease biomarkers
could be useful in the evaluation of brain microvascular
damage. J Am Geriatr Soc 2018.
Key words: albuminuria; proteinuria; kidney disease;
cerebral small vessel disease; stroke
idespread vascular injury in the brain and the ensu-
ing effect on structural and functional connectivity
are main contributors to neurocognitive dysfunction.
Cerebral small vessel disease (SVD) is responsible for more
than 20% of strokes, which are the major contributor to
vascular dementia and a potential pathogenetic mechanism
to Alzheimer’s disease.
Investigation of cerebral SVD is
possible by observing its effects on the brain parenchyma
using magnetic resonance imaging (MRI), including white
matter hyperintensities (WMHs), lacunar infarcts (LIs),
cerebral microbleeds (CMBs), and enlarged perivascular
Because of the unity of the vasculature, SVD is consid-
ered a systemic disorder,
and microcirculatory damage in
other organs could accompany its occurrence in the brain.
The kidney and the brain have similar hemodynamic prop-
erties, with low resistance and high circulatory ﬂow.
Chronic kidney disease (CKD) has been associated with
cerebral SVD and cognitive decline,
but in advanced dis-
ease stages, factors related to impaired clearance could be
the main contributors and confound the association
between CKD and SVD.
Albuminuria is an early marker of kidney disease,
corresponding to a subclinical time-point when the esti-
mated glomerular ﬁltration rate (eGFR) may have not
yet been affected.
Albuminuria has been associated
with coronary artery disease, stroke, and cardiovascular
From the *Department of Hygiene, Epidemiology and Medical Statistics;
Second Department of Neurology, “Attikon” University Hospital,
Medical School, National and Kapodistrian University of Athens, Athens,
Department of Neurology, University of Tennessee Health
Science Center, Memphis, Tennessee.
Address correspondence to Marios K. Georgakis, Department of Hygiene,
Epidemiology and Medical Statistics, Medical School, National and
Kapodistrian University of Athens, Mikras Asias 75, 11527, Athens,
Greece. E-mail: email@example.com
© 2017, Copyright the Authors
Journal compilation © 2018, The American Geriatrics Society 0002-8614/18/$15.00
damage. J Am Geriatr Soc 66:509–517, 2018.
JAGS 66:509–517, 2018
2018, Copyright the Authors
2018, The American Geriatrics Society 0002-8614/18/$15.00