Original Paper
Cerebrovasc Dis 2011;31:271–277
DOI: 10.1159/000322155
Chronic Kidney Disease in Patients with Acute
Intracerebral Hemorrhage: Association with Large
Hematoma Volume and Poor Outcome
Noa Molshatzki David Orion Rakefet Tsabari Yvonne Schwammenthal
Oleg Merzeliak Maya Toashi David Tanne 
Stroke Center, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center,
Tel Hashomer, Israel
Key Words
Intracerebral hemorrhage, outcome ⴢ Chronic kidney
disease
Abstract
Background: Chronic kidney disease (CKD) is associated
with both a risk of adverse vascular outcome and a risk of
bleeding. We have tested the hypothesis that in the setting
of an acute intracerebral hemorrhage (ICH), CKD is associat-
ed with poor outcome and with larger hematoma volume.
Methods: We examined the association between CKD and
ICH characteristics and outcome within a prospective cohort
study of consecutive patients hospitalized with an acute
stroke and followed for 1 year. CKD was categorized by the
estimated baseline glomerular filtration rate into moderate/
severe impairment (!45), mild impairment (45–60) and no
impairment (160 ml/min/1.73 m2). Results: Among 128 pa-
tients with an ICH (mean age = 71.7 8 12.3 years, 41.4%
women) 46.1% had CKD (23.4% mild and 22.7% moderate/
severe). Patients with moderate/severe impairment had 1 4-
fold adjusted hazard ratio for mortality over 1 year (4.29; 95%
CI = 1.69–10.90) compared to patients with no impairment.
The hematoma volumes [median (25–75%)] were 15.3 ml
(5.4–37.5) in patients with no impairment, 16.6 (6.8–36.9) in
© 2010 S. Karger AG, Basel
1015–9770/11/0313–0271$38.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Received: July 30, 2010
Accepted: October 12, 2010
Published online: December 21, 2010
mild impairment and 50.2 (10.4–109.1) in moderate/severe
impairment (p = 0.009). The location of the hematoma was
lobar in 12% with no impairment, 17% with mild impairment
and 39% with moderate/severe impairment (p = 0.02). Pa-
tients with moderate/severe impairment exhibited a 2.3-
fold higher hematoma volume (p = 0.04) and a 16-fold high-
er odds of lobar location (95% CI = 1.59–24.02) as compared
to no impairment. Further adjustment for antiplatelet use
and for presence of leukoaraiosis attenuated the association
with hematoma volume (p = 0.15), while moderate/severe
impairment was associated with an adjusted OR of 5.35 (95%
CI = 1.18–24.14) for lobar location. Conclusions: Presence of
moderate/severe CKD among patients with ICH is associated
with larger, lobar hematomas and with poor outcome.
Copyright © 2010 S. Karger AG, Basel
Intracerebral hemorrhage (ICH) is associated with
poor outcome, with a mortality rate approaching 50%
and little effective treatment [1]. In the setting of an ICH,
a severe neurological deficit at presentation, a large vol-
ume of the hematoma, hematoma location and the pres-
ence of ventricular blood are factors that have been con-
sistently identified as predictive of poor outcome [1–3].
There is growing evidence for an association between
Prof. David Tanne
Stroke Center, Department of Neurology
The Chaim Sheba Medical Center
Tel Hashomer 52621 (Israel)
Tel. +972 3 530 2069, Fax +972 3 635 6087, E-Mail tanne @ post.tau.ac.il
chronic kidney disease (CKD) and adverse cardiovascu-
lar events [4–6]. CKD is associated also with increased
risk of bleeding after coronary interventions [7–9], acute
myocardial infarction [10], coronary artery bypass sur-
gery [11] and use of anticoagulation [12], as well as with
cerebral small-vessel disease, white matter hyperintensi-
ties and microbleeds [13–16]. We have, therefore, hypoth-
esized that in the setting of ICH, CKD is associated with
larger initial hematoma volume and poor outcome. Our
aim was to investigate among patients with ICH the as-
sociation between presence of CKD and its severity and
hematoma volume, location and all-cause mortality.
Methods
Design
Data were derived from a longitudinal cohort study of hospi-
talized patients including 1,086 consecutive patients (136 with
ICH, 746 with ischemic stroke and 203 with a transient ischemic
attack) admitted from March 2001 to June 2002 throughout a
large medical center with a catchment area of about 500,000 peo-
ple. The patients were evaluated systematically for risk factors,
stroke severity and type. Severity of stroke was assessed using the
National Institute of Health stroke scale [17].
Mortality data were derived from the Israeli Population Reg-
istry and were available for all patients. A clinical evaluation and
personal interview was performed with patients and/or proxies
after 1 month and a phone follow-up interview after 1 year, after
obtaining informed consent. The study was approved by the local
Institutional review board.
ICH was differentiated from ischemic stroke by the results of
the baseline head CT scan. Among the patients with ICH (n =
136), 8 were excluded since baseline glomerular filtration rate es-
timation (eGFR) was missing, and therefore the current study
group consisted of 128 patients. Digital data of the baseline head
CT available for hematoma volume calculation were missing for
23 patients, therefore for hematoma volume analyses the study
group consisted of 105 patients.
Data Collection
Serum creatinine measurements were performed at a central
laboratory using the Jaffe assay. GFR was estimated based on a
single creatinine measurement performed at baseline using the
4-variable Modification of Diet in Renal Disease formula: GFR =
186 ! (Scr)–1.154 ! (age)–0.203 ! (0.742 if the subject is female) [18].
CKD was defined following the National Kidney Foundation def-
inition as kidney damage, reflected by an estimated eGFR of !60
ml/min/1.73 m2 of body surface area and was further categorized
into mild-moderate reduction of GFR of 45–60 and moderate-
severe reduction of !45 ml/min/1.73 m2. This further categoriza-
tion is a modification of the National Kidney Foundation classi-
fication scheme, chosen based on prior studies in patients with
cardiovascular disease [19]. The first available international nor-
malized ratio (INR) value upon medical presentation was record-
ed. There were 8 patients without INR results. Because none of
these patients received anticoagulation, they were assigned INR
272 Cerebrovasc Dis 2011;31:271–277
values of 1.0. The INR groups were defined as: INR !1.2, INR
1.2–2.0, INR 12.0.
Imaging Analysis
CT scans were downloaded directly to a workstation and were
reviewed by a study investigator blinded to clinical data and CKD
status. CT scans were analyzed via volumetric analysis using Sci-
on Image software (Scion Corp, Frederick, Md., USA), a public
domain software modified from the NIH Image software (Scion
Corporation, 2000–2001). Hemorrhages were traced on each head
CT slice and volumes were calculated by multiplying by slice
thickness. ICH was considered lobar in location if the origin of
the hemorrhage appeared to be in the cerebral hemispheres super-
ficial to the deep gray matter structures. Hemorrhages originat-
ing in the thalamus and basal ganglia were considered ‘deep’ in
location, and those originating in the brainstem or cerebellum
were regarded as infratentorial. Intraventricular hemorrhage was
categorized as mild (blood in third ventricle or less than one third
of 1 lateral ventricle) or moderate/severe.
Statistical Analysis
Kidney function was categorized into 3 groups: moderate/se-
vere impairment (!45), mild impairment (45–60) and no impair-
ment (1 60 ml/min/1.73 m2). Unless mentioned otherwise, eGFR
entered all models as categorical variable with eGFR 1 60 ml/
min/1.73 m2 as the reference group. Univariate associations be-
tween eGFR categories and other baseline demographic and clini-
cal variables were evaluated with analysis of variance and ␹2 tests.
The relation between eGFR groups and survival rates after a 1-year
follow-up is presented as Kaplan-Meier curves and compared us-
ing the log rank test. The effect on 1-year survival is modeled using
hazard ratio (HR) calculations from the Cox proportional hazard
model. The model included eGFR categories and was adjusted for
age, gender, INR groups, hypertension, hematoma volume (log
transformed), lobar location, prior disability and NIH stroke scale.
In order to keep the proportional hazard assumption prior disabil-
ity and NIH stroke scale entered the model as stratification vari-
ables. Hematoma volumes were log transformed to approximate
normality. To identify potential association between eGFR groups
and hematoma volume, linear regression analyses were performed.
The unadjusted model included only eGFR groups as explanatory
variables and the adjusted model included the following addition-
al variables: age, gender, INR groups and hypertension (the refer-
ent value for the adjusted linear model was: male, INR !1.2 and no
hypertension). Unadjusted and adjusted odds ratios (ORs) from
logistic regression models were used to examine potential rela-
tionships between eGFR groups and lobar location of hematoma.
All models were repeated further adjusting for antiplatelet use and
cerebral leukoaraiosis. Analyses were performed with R statistical
software version 2.8.1.
Results
Among the 128 patients with ICH, the mean age was
71.7 8 12.3 years and 41.4% were women. Overall, the
proportion of patients having CKD was 46.1% (23.4%
mild and an additional 22.7% moderate/severe). Baseline
Molshatzki et al.
 Table 1. Baseline characteristics by eGFR groups

eGFR groups, ml/min/1.73 m2 p value

>60 (n = 69) 45–60 (n = 30) <45 (n = 29)

Age, years 70.4810.9 72.5814.9 73.9812.9 0.40

Female 29.0 63.3 48.3 <0.01
Hypertension 56.5 90.0 79.3 <0.01
Dyslipidemia 17.4 23.3 10.7 0.45
Diabetes 14.5 36.7 25.0 0.05
Current smoking 17.5 20.0 10.0 0.83
Prior stroke 26.1 30.0 37.9 0.50
Anemia 17.9 23.3 25.0 0.69
Malignancy 7.2 6.7 10.7 0.82
Prior disability 33.3 36.7 59.3 0.06
Coronary heart diseasea 20.3 16.7 31.0 0.37
Other cardiac diseaseb 21.7 20.0 34.5 0.34
Antiplatelet usec 29.0 23.3 54.2 0.04
Warfarin usec 13.0 17.2 12.0 0.82
Statin usec 8.7 17.2 12.5 0.40
NIH stroke scale
<5 22.4 10.0 14.8 0.52
6–10 13.4 16.7 7.4
>11 64.2 73.3 77.8
INR groups
<1.2 71.9 80.0 75.0 0.61
1.2–2 21.9 10.0 14.3
>2 6.2 10.0 10.7
First systolic BP, mm Hg 176.2827.6 181.0825.5 181.9839.2 0.62
First diastolic BP, mm Hg 87.8815.2 92.6825.0 89.3823.9 0.61
Leukoaraiosis 56.9 72.4 92.6 <0.01

Values are means 8 SD for continuous variables, percentages for categorical variables. BP = Blood pressure.
a
Angina pectoris and/or myocardial infarction. b Congestive heart failure, atrial fibrillation or valvular
heart disease. c Use in the week prior to the ICH.

characteristics of the study cohort across the 3 eGFR
groups are shown in table 1. The 3 groups differed (p !
0.05) in the rate of women, hypertension and prior use of
antiplatelets and in the rates of leukoaraiosis. There were
no significant differences in onset to CT time and admis-
sion to CT time between the 3 groups (p 1 0.05).
The mortality rates after 1 month were 41% in patients
with no impairment, 30% in mild impairment and 83%
in moderate/severe impairment, and after 1 year 48 ver-
sus 40 and 86%, respectively (p ! 0.001 for both). Kaplan-
Meier 1-year survival curves by eGFR groups are depict-
ed in figure 1 (p ! 0.001, log rank). Of note, most of the
mortality (⬃90%) occurred within the first 2 months af-
ter the event. Cox proportional hazard models for mor-
tality over 1 year are presented in table 2. Patients with
moderate/severe impairment had a nearly 6-fold adjust-
ed HR for mortality over 1 year (5.82; 95% CI = 2.40–
14.09) versus patients with no impairment. Further ad-
justment for antiplatelet use and cerebral leukoaraiosis
only mildly attenuated these associations (HR = 4.29;
95% CI = 1.69–10.90) versus patients with no impair-
ment.
The quartiles, dispersion, skewness and outliers of he-
matoma volume by eGFR groups are plotted in box plots
in figure 2a. Patients with no impairment had hematoma
volumes of [median (25–75%)] 15.3 ml (5.4–37.5), those
with mild impairment of 16.6 (6.8–36.9) and those with
moderate/severe impairment of 50.2 (10.4–109.1; p =
0.009; Kruskal-Wallis test). The location of the hematoma
was lobar among 39% of the patients with moderate/se-
vere impairment versus 17% with mild impairment and
12% with no impairment (p = 0.02; fig. 2b). The percent-

Chronic Kidney Disease in Intracerebral Cerebrovasc Dis 2011;31:271–277 273

Hemorrhage
Table 2. Cox proportional hazard model for mortality over 1 year after ICH

Unadjusted model Model Aa Model Bb

HR p value HR p value HR p value

eGFR >60 ml/min/1.73 m2 1.00 1.00 1.00

eGFR 45–60 ml/min/1.73 m2 0.86 (0.43–1.72) 0.67 0.73 (0.33–1.6) 0.43 0.76 (0.35–1.65) 0.48
eGFR <45 ml/min/1.73 m2 4.06 (2.24–7.33) <0.001 5.82 (2.40–14.09) <0.01 4.29 (1.69–10.90) <0.01

Figures in parentheses are 95% CI.

a
Adjusted for age, gender, hypertension, INR groups, hematoma volume (after log transformation), lobar location, prior disability
and NIH stroke scale. b Adjusted in addition for antiplatelet use and leukoaraiosis.

Table 3. Linear regression model of initial hematoma volume

Variable Unadjusted model Model Aa Model Bb

estimate AntiLog p value estimate AntiLog p value estimate AntiLog p value

Intercept 2.45 11.64 <0.001 1.90 6.66 0.05 1.59 4.90 0.12
eGFR 45–60 ml/min/1.73 m2 0.21 1.23 0.55 0.04 1.04 0.92 0.05 1.06 0.89
eGFR <45 ml/min/1.73 m2 1.00 2.71 0.01 0.82 2.27 0.04 0.65 1.91 0.15

The referent value for the unadjusted model is eGFR >60 ml/min/1.73 m2, for the adjusted model: male, INR <1.2 and no hyperten-
sion.
a Adjusted for age, gender, hypertension and INR groups. b Adjusted in addition for antiplatelet use and leukoaraiosis.

age of any intraventricular extension was 62% among pa-

1.0 eGFR >60 tients with moderate/severe impairment versus 35% with
eGFR 45–60 mild impairment and 38% with no impairment (p = 0.08;
eGFR <45 fig. 2c). Data regarding hematoma growth were available
0.8
for only a subset of 38 patients, with median (IQR) growth
of 10.1 ml (3.9–16.3) among patients with moderate/se-
0.6 vere impairment versus 1.3 (–0.5 to 7.8) with mild impair-
Survival

ment and 0.2 (–3.0 to 3.8) with no impairment (p = 0.19;

Kruskal-Wallis test).
0.4
The estimated associations between eGFR groups and
hematoma volume and lobar location are presented in ta-
0.2 ble 3 and 4, respectively. In both types of model signifi-
cant associations were observed with moderate/severe
impairment as compared to no impairment in both un-
0
adjusted models and in those adjusted for age, gender,
0 2 4 6 8 10 12 hypertension and INR groups (p ! 0.05 for all). In the
Time (months)
adjusted model, patients with moderate/severe impair-
ment have a 2.3-fold higher hematoma volume compared
to the referent (table 3; p = 0.04), and a 16-fold higher
Fig. 1. Kaplan-Meier estimates for cumulative 1-year survival
function for all-cause mortality according to categories for eGFR
odds of lobar location (table 4; 95% CI = 1.59–24.02). Fur-
groups (number of patients at risk: eGFR 1 60 = 49, eGFR 45– ther adjustment for antiplatelet use and for cerebral leu-
60 = 29 and eGFR !45 = 26). Log-rank test, p ! 0.001. koaraiosis attenuated the association with hematoma vol-

274 Cerebrovasc Dis 2011;31:271–277 Molshatzki et al.

Table 4. Logistic regression model for lobar hematoma location

Unadjusted model Model Aa Model Bb

OR OR OR

eGFR >60 ml/min/1.73 m2 1.00 1.00 1.00

eGFR 45–60 ml/min/1.73 m2 1.53 (0.42–5.53) 2.14 (0.46–9.94) 1.87 (0.41–8.61)
eGFR <45 ml/min/1.73 m2 4.58 (1.43–14.66) 6.18 (1.59–24.02) 5.35 (1.18–24.14)

Figures in parentheses are 95% CI.

aAdjusted for age, gender, hypertension and INR groups. b Adjusted in addition for antiplatelet use and leukoaraiosis.

250 Lobar Deep Infratentorial

100

200
Hematoma volume (ml)

80

150
60

Percentage
100
40

50
20

a eGFR >60 eGFR 45–60 eGFR <45 b eGFR >60 eGFR 45–60 eGFR <45

Moderate/severe Mild No
100

80

60
Percentage

40

Fig. 2. ICH imaging characteristics according to categories for 20

eGFR groups. a Box plot of hematoma volume by eGFR groups
(Kruskal-Wallis test, p = 0.009). b Bar chart of percentage of he-
matoma location by eGFR groups (␹2 test for lobar vs. other loca-
tion, p = 0.02). c Bar chart of percentage of intraventricular exten- c eGFR >60 eGFR 45–60 eGFR <45
sion by eGFR groups (␹2 test for any vs. no intraventricular exten-
sion, p = 0.08).

Chronic Kidney Disease in Intracerebral Cerebrovasc Dis 2011;31:271–277 275

Hemorrhage
ume (p = 0.15), while moderate/severe impairment was
associated with an adjusted OR of 5.35 (95% CI = 1.18–
24.14) for lobar location. None of the variables used for
adjustment were found to be significantly related to the
outcome in these models (data not tabulated).
Discussion
Our main findings are that patients with moderate/
severe impairment in kidney function exhibit nearly
6-fold increased hazards for mortality over 1 year com-
pared to subjects with no impairment. They also exhibit
a 2.7-fold higher hematoma volume and have increased
odds of lobar location.
Patients with moderate/severe impairment in kidney
function had larger hematoma volumes, enough to pro-
duce a potent effect on mortality in this group. Davis et al.
[20] have estimated that for each 1-ml increase in baseline
hematoma volume, the hazard ratio of dying increased by
1%. Our median difference of 35 ml in hematoma volume
between patients with moderate/severe impairment ver-
sus no impairment is compatible with the substantially
higher mortality rates observed. Patients with moderate/
severe impairment also exhibited a 1.6-fold higher rate of
intraventricular extension, an additional factor that con-
sistently leads to poor outcome after ICH [21].
An excess risk of bleeding in CKD patients may be at-
tributed in part to disturbances in the coagulation system
coupled with altered response to medications [22, 23].
CKD is also associated with cerebral small-vessel disease
and with white matter hyperintensity, highlighting the
growing importance of kidney disease as a possible deter-
minant of cerebrovascular disease and/or as a marker of
microangiopathy and ultimately with long-term survival
[13, 14, 16]. Indeed, kidney and brain are end organs that
are vulnerable to hypertensive damage [24], and a higher
rate of cerebral microbleeds is identified by MRI in pa-
tients with acute ischemic stroke [15]. Patients with mod-
erate/severe CKD in our cohort were more often pre-
scribed antiplatelets and more often had cerebral leu-
koariosis. Leukoariosis [25] and use of antiplatelets [26]
were previously found to be associated with higher mor-
tality. Further adjustment somewhat attenuated the as-
sociations examined, suggesting the effect of antiplatelets
and cerebral leukoaraiosis may mediate in part the asso-
ciation observed.
The observed association between CKD and lobar
location of ICH deserves consideration. White matter
changes related to CKD are associated with larger ICH
276 Cerebrovasc Dis 2011;31:271–277
volumes and are frequent in deep as well as in lobar loca-
tion [27, 28]. There is, however, also the possibility of mis-
classification of larger subcortical ICH extending to the
cortex.
The limitations of our study are similar to those of oth-
er single-center registry studies. The data are based on a
relatively large cohort of consecutive unselected patients
admitted with acute stroke, but the group of ICH is fairly
small. The assessment is, however, based on a ‘real-world’
population reflected by the nearly 50% proportion of pa-
tients with CKD, comparable to that observed by Oksala
et al. [16]. Second, the GFR levels are estimated based on a
single creatinine measurement performed at baseline. Dif-
ferences between the estimated and true GFR may have led
to misclassification of some subjects, although misclas-
sification would likely lead to underestimation of the
strength of the associations. We have focused our analyses,
however, on eGFR in the borderline or kidney disease
range, for which the estimation equations are more accu-
rate. Third, we may not have adjusted for all potential
sources of confounding, although we adjusted for multiple
variables. Finally, the ability to predict hematoma growth
after ICH has important prognostic implications [20].
However, we only examined hematoma growth in a small
subset of patients and the association between CKD and
hematoma growth deserves further investigation.
In conclusion, we present data on the association be-
tween presence of CKD and its severity and hematoma
volume, hematoma location and all-cause mortality. We
have found that CKD is associated with larger hematoma
volume and lobar location as well as with intraventricular
extension and that it is a strong independent predictor of
mortality among patients with ICH. These findings are
novel but require validation in other large prospective co-
horts.
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