Full text of DOI:10.1053/ajkd.2001.27694

Familial Clustering of Ruptured Intracranial Aneurysms
in Autosomal Dominant Polycystic Kidney Disease
Mark M. Belz, MD, Richard L. Hughes, MD, William D. Kaehny, MD, Ann M. Johnson, MS,
Godela M. Fick-Brosnahan, MD, Michael P. Earnest, MD, and Patricia A. Gabow, MD
●
Ruptured intracranial aneurysm (RICA) is a life-threatening complication of autosomal dominant polycystic
kidney disease (ADPKD). A family history of RICA may be a risk factor for RICA. Six hundred eight adult members of
99 ADPKD families were interviewed, and family pedigrees were constructed. Individuals were classified as having
definite, probable, or possible RICAs from evidence and history obtained in interviews. Central nervous system
CNS) events not consistent with RICA were classified as other CNS events. Seventy-seven CNS events occurred in
06 subjects with ADPKD (8.5%) versus 13 events in 823 subjects without ADPKD (1.6%; P < 0.0001). No event in
1
(
9
subjects without ADPKD was consistent with an RICA. Twenty-seven other (non-RICA) CNS events occurred in
subjects with ADPKD (3%) versus 13 events in subjects without ADPKD (1.6%; P ؍ 0.05). The frequency of RICA was
increased in subjects with ADPKD: 21 definite RICAs in subjects with ADPKD (2%) versus none in subjects without
ADPKD (P < 0.001); 28 definite and probable RICAs in subjects with ADPKD (3%) versus none in subjects without
ADPKD (P < 0.001); and 50 definite, probable, and possible RICAs in subjects with ADPKD (5.5%) versus none in
subjects without ADPKD (P < 0.001). The null hypothesis that RICAs are randomly distributed among subjects with
ADPKD was tested for definite RICAs (n ؍ 21), definite and probable RICAs (n ؍ 28), and definite, probable, and
possible RICAs (n ؍ 50). In the three categories, the null hypothesis was rejected at P less than 0.05, P less than
0
.05, and P less than 0.005, respectively. Vascular CNS events occurred more frequently in ADPKD than non-
ADPKD family members, and clustering of RICAs occurred in families with ADPKD.
2001 by the National Kidney Foundation, Inc.
©
INDEX WORDS: Autosomal dominant polycystic kidney disease (ADPKD); intracranial aneurysms (ICAs); ruptured
intracranial aneurysms (RICAs).
UTOSOMAL DOMINANT polycystic kid-
American populations have found rates of ICAs
in individuals with ADPKD of 4% to 11.7% in
contrast to the 1% prevalence in the general
A
ney disease (ADPKD) is a systemic dis-
ease with both cystic and noncystic manifesta-
tions. Perhaps the most devastating noncystic
manifestation is intracranial aneurysm (ICA).
Individuals with ADPKD worldwide have an
increased frequency of ICAs compared with the
general population, with estimates of prevalence
among individuals with ADPKD ranging from
1
-3,5
population.
This increased ICA frequency is of concern
because of the risk for rupture (RICA) and its
devastating consequences. Although the rupture
rate of ICAs per year is not known in ADPKD,
4% to 7% of individuals with ADPKD have
subarachnoid hemorrhage (SAH) as the cause of
1
-4
4
% to 41%. Large prospective studies in North
6
-9
death. The frequency of ICAs and their role in
mortality inADPKD raise the question of screen-
ing all patients with ADPKD for this manifesta-
tion. Two decision analyses reached contradic-
tory conclusions regarding screening of
From the Departments of Medicine and Neurology, Uni-
versity of Colorado Health Sciences Center; and the Medi-
cal Service, Veterans Affairs Medical Center, Denver, CO.
Received January 17, 2001; accepted in revised form May
1
0-12
asymptomatic individuals with ADPKD.
4
, 2001.
Therefore, identifying subsets of individuals with
ADPKD at high risk for RICA would simplify
decisions about screening.
Supported in part by grant no. 5 P01 DK34039, human
polycystic kidney disease, from the Department of Health
and Human Services, Public Health Service, National Insti-
tute of Diabetes and Digestive and Kidney Diseases; and
grant no. MORR-00051 from the Clinical Research Center,
General Clinical Research Centers Research Program of the
Division of Research Resources, National Institutes of Health.
Address reprint requests to Godela M. Fick-Brosna-
han, MD, Polycystic Kidney Disease Research Group,
200 E Ninth Ave, #C283, Denver, CO 80262. E-mail:
godela.fick-brosnahan@uchsc.edu
2001 by the National Kidney Foundation, Inc.
272-6386/01/3804-0007$35.00/0
doi:10.1053/ajkd.2001.27694
In the general population, several studies have
shown an increased prevalence of ICAs in first-
degree relatives of individuals who have had an
13-19
ICAor SAH.
Aprospective study of individu-
als with ADPKD using magnetic resonance an-
giography (MRA) found that 22% of 27 subjects
with a family history of ICA or SAH had an
asymptomatic ICA compared with 5% of 56
4
©
0
2
subjects who lacked such a family history. Eigh-
770
American Journal of Kidney Diseases, Vol 38, No 4 (October), 2001: pp 770-776

CLUSTERING OF RUPTURED ANEURYSMS IN ADPKD
771
teen percent to 22% of individuals with ADPKD
with an ICA have a family history of ICA or one
with medical records that described a clinical presentation
and course likely to be from an RICAand not consistent with
an alternative diagnosis, such as migraine, trauma, arterio-
venous malformation, or ischemic stroke. Typically, either
neuroimaging or spinal fluid testing (especially in the pre–
computed tomographic scan era) confirmed SAH. Patients
with possible RICA met the same clinical criteria, but
supporting medical records were not available and medical
information was relayed verbally by the patient or family.
This information had to be quite compelling and typically
was very detailed (eg, “According to my mother, my grand-
father had a right middle cerebral artery aneurysm that
ruptured and killed him. He grabbed his head, fell over, and
died.”). Intraparenchymal hemorrhages, cerebral infarction,
and nonspecific cerebrovascular accident or stroke were not
included as possible RICAs. Subjects with these events were
placed into the “other vascular CNS event” category.
Frequencies of vascular CNS events, RICAs, and other
vascular CNS events were compared between ADPKD and
non-ADPKD family members by means of chi-square analy-
sis. Because there was a large number of families with small
numbers of affected members, Fisher’s exact test using
Monte Carlo sampling was used to test the null hypothesis
that ICAs are randomly distributed among family members
with ADPKD (StatXact software; Cytel Software Corp,
Cambridge, MA). Using this method, more than 10,000
computer trials were performed in which the total number of
RICAs was randomly distributed among ADPKD members
of families of the same configuration as the families in our
data set. It was recorded how often the test families showed
the same or greater degree of clustering of RICAs seen in
actual families. P less than 0.05 using this method would
indicate that this degree of clustering occurred in less than
2
0,21
highly suggestive of ICA.
These findings
logically generate the important clinical ques-
tion: Does the frequency of RICA show this
familial clustering? This has been suggested by
2
1,22
several investigators.
A retrospective study
of RICAs in families in the ADPKD database at
the University of Colorado (Denver, CO) was
conducted.
METHODS
During the period from June 1, 1985, through January 30,
1
990, a total of 608 consecutive adult (aged Ն18 years)
members of 199 families with ADPKD who participated in
the ongoing natural history study of ADPKD at the Univer-
sity of Colorado were interviewed by a single nurse practitioner,
genetic counselor, or physician in the Clinical Research
Center at the University of Colorado Health Sciences Cen-
ter. The study protocol was approved by the Colorado
Multiple Institutional Review Board. Informed consent was
obtained from each subject participating in this study.
A formalized interview of each subject was conducted,
and detailed family pedigrees were constructed. Questions
were asked about personal or family occurrence of acute
neurological events, strokes, intracranial hemorrhages, and
RICAs in subjects with and without ADPKD in the pedi-
grees. Subjects with ADPKD were not selected for a per-
sonal or family history of ICA. The diagnosis of ADPKD for
those subjects studied at the University of Colorado Health
Sciences Center was based on detection by ultrasonography
of a total of five or more cysts in both kidneys and usually a
family history of polycystic kidney disease. ADPKD was
diagnosed in 384 subjects by these criteria. In 224 subjects,
the diagnosis of ADPKD was excluded by these criteria.
Five hundred twenty-two additional individuals were consid-
ered to have ADPKD based on historical data obtained from
relatives who were interviewed as described.
5
% of trials.
RESULTS
Classification of patient groups is shown in
Fig 1. Nine hundred six family members with
ADPKD were identified, along with 823 family
members withoutADPKD. Three hundred eighty-
four subjects with ADPKD were studied, and the
diagnosis was confirmed at the University of
Colorado Health Sciences Center, defined previ-
ously. Two hundred twenty-four subjects without
ADPKD were also studied at the University of
Colorado Health Sciences Center. A total of 77
vascular CNS events occurred in the 906 sub-
jects with ADPKD (8.5%) compared with 13
vascular CNS events in 823 subjects without
ADPKD (1.6%; P Ͻ 0.0001). None of the vascu-
lar CNS events in subjects without ADPKD was
consistent with RICA. When definite, probable,
and possible RICAs are excluded, there were 27
other vascular CNS events in 906 subjects with
ADPKD (3%) in comparison to 13 vascular CNS
Additional information about all subjects said to have had
acute central nervous system (CNS) events was obtained by
reviewing autopsy reports, surgical reports, radiological re-
ports and films, hospital records, and physician records. If
these were unavailable, physicians, subjects, and other fam-
ily members were interviewed to substantiate the history.
Relatives in the pedigrees with and without ADPKD for
whom little personal and no medical information were
available were not included in the study.
Only subjects with or without ADPKD who were aged 18
years or older and identified by name and age in interviews
or documents in the database were included. No subject aged
younger than 18 years had a nontraumatic acute vascular
CNS event. Nontraumatic acute vascular CNS events were
classified as definite RICA, probable RICA, possible RICA,
and other vascular CNS event. Categorization was per-
formed by examination of case histories by two staff neurolo-
gists (R.L.H. and M.P.E.) blinded to the ADPKD status of
each subject. Definite RICA required a clinical episode of
SAH, with documentation of SAH and RICA by neuroimag-
ing, surgery, or autopsy. Probable RICA included patients

772
BELZ ET AL
Table 1. Distribution and Classification of RICA
Among 906 Subjects With ADPKD From
199 Families
No. of Family
Members with
ADPKD
Definite
RICA
Probable
RICA
Possible
RICA
Total No.
of Families
No family member with an RICA
1
2
3
4
5
6
7
8
9
0
2
4
5
5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
36
37
21
23
16
15
3
7
2
3
3
1
1
1
1
2
1
2
1
Total:
65
6
0
0
0
170
Single family member with an RICA
1
2
2
3
4
4
5
6
7
7
0
1
2
3
0
0
1
1
0
1
0
0
0
1
1
0
0
1
0
1
0
0
1
0
0
0
0
0
0
0
0
0
1
0
0
0
0
0
1
1
1
0
0
1
1
0
1
1
2
1
1
2
2
1
1
1
1
2
1
1
1
1
1
3
Total:
129
Fig 1. Distribution and classification of subjects
and events among the 199 families with ADPKD. Vas-
cular CNS events were classified as definite, probable,
or possible RICA or other vascular CNS events depend-
ing on history and documentation obtained.
8
2
8
18
Multiple family members with an RICA
3
5
5
6
9
1
1
3
1
2
2
1
0
0
2
0
0
2
0
0
0
0
2
0
3
0
0
0
0
0
1
3
0
0
2
2
0
2
4
0
1
1
1
1
1
1
1
1
1
1
1
events in 823 subjects without ADPKD (1.6%;
P ϭ 0.05).
The distribution of RICAs among the 199
families is listed in Table 1. There were 21
definite RICAs in the 906 subjects with ADPKD
2%) and none among the 823 subjects without
ADPKD (P Ͻ 0.001). If definite and probable
RICAs are included, there were 28 RICAs in the
06 subjects withADPKD (3%) and none among
1
1
11
13
13
25
(
Total:
12
9
1
13
5
14
11
the 823 subjects without ADPKD (P Ͻ 0.001). If
the three categories of definite, probable, and
possible RICAs are included, there were 50

CLUSTERING OF RUPTURED ANEURYSMS IN ADPKD
773
Table 2. Occurrence of RICA in Subjects With Versus Without ADPKD for Categories of Definite, Definite and
Probable, and Definite, Probable, and Possible RICA
Subjects with ADPKD
n ϭ 906)
Subjects Without ADPKD
(
(n ϭ 823)
P Value
Definite RICA (%)
Definite and probable RICA (%)
Definite, probable, and possible RICA (%)
21 (2)
28 (3)
50 (5.5)
0(0)
0(0)
0(0)
Ͻ0.001
Ͻ0.001
Ͻ0.001
NOTE. Values expressed as number (percent).
RICAs in the 906 subjects with ADPKD (5.5%)
and none among the 823 subjects without
ADPKD (P Ͻ 0.001; Table 2).
and possible RICAs (n ϭ 50). In the three
categories, the null hypothesis was rejected at P
less than 0.05, P less than 0.05, and P less than
0.005, respectively, indicating a nonrandom dis-
tribution of RICAs among the families. Thus,
clustering of RICAs occurs in ADPKD families
to a greater degree than expected by chance
alone.
Figure 2 shows the distribution of RICAs
among families for each category. When definite
RICAs are included, 5 of the 199 families (2.5%)
with two or more RICAs accounted for 52% of
RICAs, and only 15 families (7.5%) accounted
for all RICAs. When definite and probable RICAs
are included, 7 of the 199 families (3.5%) with
two or more RICAs accounted for 61% of RICAs,
and only 18 families (9.0%) accounted for all
RICAs. When definite, probable, and possible
RICAs are included, 11 of 199 families (5.5%)
with two or more RICAs accounted for 64% of
RICAs, and 29 families (14.6%) accounted for
all RICAs. This suggests a nonrandom familial
distribution of RICAs.
DISCUSSION
This study examined a large population of
well-studiedADPKD families to assess the occur-
rence of RICAs and other vascular CNS events.
This provides important information to clini-
cians caring for these patients. This study showed
an increased risk for all types of vascular CNS
events in subjects with ADPKD. The total per-
centage (frequency) of vascular CNS events in
subjects with ADPKD (8.5%) exceeded the total
percentage (frequency) of vascular CNS events
in subjects without ADPKD (1.6%; P Ͻ 0.0001).
When definite, probable, and possible RICAs are
excluded, the total percentage (frequency) of
The null hypothesis that RICAs are randomly
distributed among subjects with ADPKD in the
1
99 families studied was tested for the following
categories: definite RICAs (n ϭ 21), definite and
probable RICAs (n ϭ 28), and definite, probable,
Fig 2. Distribution of
RICAs among the 199 fami-
lies with ADPKD. Vascular
CNS events were classified
as definite, probable, or pos-
sible RICA or other vascular
CNS events depending on
history and documentation
obtained.

774
BELZ ET AL
nonaneurysmal vascular CNS events in subjects
with ADPKD (3%) was greater than the percent-
age (frequency) of nonaneurysmal vascular CNS
events in subjects without ADPKD (1.6%; P ϭ
status. This would tend to make our findings of
familial clustering more robust because no sub-
ject labeled unaffected was known to have expe-
rienced an RICA. The classification system of
acute CNS events was not optimal. Although in
each case, a reasonable attempt was made to
confirm the diagnosis of RICA by reviewing
angiograms, surgical reports, or autopsy results,
such evidence was available for only 21 of 50
suspected cases in this population. Thus, events
were classified as probable as well as possible by
two blinded staff neurologists (R.L.H. and
M.P.E.). However, the finding of increased inci-
dence of RICAs in subjects with ADPKD com-
pared with controls and the statistically signifi-
cant finding of familial clustering using only
those subjects with definite RICAs makes both
these observations compelling, particularly when
this is supported by the inclusion of probable and
possible RICAs. Furthermore, the inclusion of
probable and possible RICAs makes the possibil-
ity of bias in favor of inclusion of only those
cases resulting in familial clustering less likely.
The impact of individuals excluded from data
analysis because of lack of information also is
unclear. In addition, correlations of vascular CNS
events with other clinical parameters were not
possible because in 58% of subjects with ADPKD
and 74% of subjects with RICA, baseline clinical
data, including hypertension, smoking history,
and presence of end-stage renal disease, were not
available. Despite these shortcomings, this study
indicates that clustering of RICAs likely occurs
in families with ADPKD.
0
.05). However, given the possibility that some
of the events in subjects with ADPKD labeled as
possible and probable RICAs were nonaneurys-
mal, the greater incidence of other CNS events is
likely significant and clinically important. This
increase in the occurrence of vascular CNS events
may be a consequence of the early onset of
hypertension or abnormal CNS vasculature in
individuals with ADPKD.
The percentage (frequency) of RICAs in sub-
jects with ADPKD exceeded the percentage (fre-
quency) of RICAs in subjects without ADPKD
(none) by a statistically significant amount when
definite, definite and probable, and definite, prob-
able, and possible RICAs were compared (P Ͻ
0
.001 in all three cases). Thus, this very large
study confirmed a significantly increased risk for
RICA in individuals with ADPKD compared
with unaffected family members, strongly sug-
gesting that this is a manifestation of the genetic
defect. In this regard, it is important to note that
polycystin-1 and polycystin-2 have been shown
to be present in human arterial smooth muscle of
2
3,24
cerebral arteries ; thus, abnormalities in these
proteins could alter the structural integrity of the
cerebral vasculature.
Results of the Monte Carlo analysis show that
RICAs cluster in certain families with ADPKD.
Reasons for this are not clear, but may relate to
specific ADPKD mutations or so-called modify-
ing genes, which may alter the expression of the
underlying gene mutation. Familial clustering of
RICAs has also been reported in the general
population. Recent studies of the general popula-
tion estimated the relative risk for SAH in a
first-degree relative of a patient with SAH to
Noninvasive screening with MRA or com-
puted tomographic angiography for ICAs in
asymptomatic individuals with ADPKD may be
of benefit. One decision analysis suggested that
MRAscreening for asymptomatic ICAs in young
individuals with ADPKD would increase life
expectancy and reduce the financial impact of
1
5-18
range from 1.8 to 6.6.
Results of this current
1
2
study support the notion that such clustering of
RICAs also occurs in the ADPKD population.
Limitations to this study exist. In subjects not
participating in the natural history study of
ADPKD at the University of Colorado, the diag-
nosis of ADPKD was based on historical data
obtained from relatives. However, individuals
would tend to be more likely to call an affected
family member unaffected than affected in the
absence of clear information regarding ADPKD
ADPKD on society. Another study suggested
that screening for ICAs with MRA would in-
crease the life expectancy of an asymptomatic
48-year-old individual with ADPKD by only 2
weeks; when the probability of impending ICA
rupture was 50%, screening the same individual
would increase life expectancy by more than 5
2
5
years. Thus, investigators have reached differ-
ent conclusions regarding screening for ICAwith
MRA. The benefit of screening for nonruptured

CLUSTERING OF RUPTURED ANEURYSMS IN ADPKD
775
ICAs in individuals with ADPKD depends in
part on their natural history, which is incom-
pletely understood; morbidity and mortality rates
associated with repair; and mortality rate of
RICA.
N, Matsumoto S: Polycystic kidney disease and intracranial
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. Atkinson JLD, Sundt TM Jr, Houser OW, Whisnant JP:
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6
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8
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1
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1
4 to 54 months. When considering surgical
morbidity and mortality after repair of asympto-
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1
983
1. Levey AS: Screening for occult intracranial aneu-
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2
9
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1
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