Intracranial Aneurysms In Autosomal Dominant Polycystic
Kidney Disease: A Nephrologist¡¯s Perspective
Mariusz
Niemczyk
Mariusz
Niemczyk, Department of
Immunology, Transplant Medicine and Internal Diseases; Medical University of
Warsaw; Nowogrodzka 59, 02-005 Warsaw, Poland
Correspondence to: Mariusz Niemczyk, Department of
Immunology, Transplant Medicine and Internal Diseases; Medical University of
Warsaw; Nowogrodzka 59, 02-005 Warsaw, Poland
Email: mariuszniemczyk@wp.pl
Telephone: +48 22 5021641
Fax: +48 22
5022127
Received: March 30,
2015
Revised: May 26, 2015
Accepted: May 30, 2015
Published online: June 26, 2015
ABSTRACT
Autosomal dominant
polycystic kidney disease (ADPKD) belongs to the most common genetic disorders,
and affects approximately 1 in 1,000 people in the general population. It is
well-known risk factor for intracranial aneurysms (IAs). However, universal screening
for IAs in ADPKD patients remains controversial. Nevertheless, to improve
patients¡¯ outcomes, patients at risk for IAs should be identified, screened,
and prophylactically treated if required. From the point of view of a
nephrologist, it is crucial to answer two questions: (1) which ADPKD patients
should undergo screening for IAs; and (2) how this screening should be done.
These issues are discussed in the paper.
© 2015 ACT. All
rights reserved.
Key words: Autosomal dominant polycystic kidney disease;
Intracranial aneurysms; Magnetic resonance angiography; Screening
Niemczyk M. Intracranial
Aneurysms In Autosomal Dominant Polycystic Kidney Disease: A Nephrologist¡¯s
Perspective. Journal of Nephrology Research 2015; 1(1): 15-18 Available from: URL:
http://www.ghrnet.org/index.php/jnr/article/view/1187
Abbreviations
ABPM: ambulatory
blood pressure monitoring;
ADPKD: autosomal
dominant polycystic kidney disease;
AH: arterial
hypertension;
CTA: computed
tomography angiography;
ESRD: end-stage
renal disease;
IA: intracranial
aneurysm;
MR: magnetic
resonance;
MRA: magnetic
resonance angiography
INTRODUCTION
Autosomal dominant polycystic kidney disease (ADPKD) belongs to the
most common genetic disorders, and affects approximately 1 in 1,000 people in
the general population. The disease is due to the mutation in one of two genes:
PKD1 in type 1, or PKD2 in type 2 of ADPKD. Mutation of PKD1 is more prevalent
and causes 85% of cases of the disease. In a large proportion of patients,
ADPKD leads to end-stage renal disease (ESRD)[1]. The average age of
ESRD depends on the type of the disease and amounts to 58.1 years in type 1,
and 79.7 years in type 2[2]. Due to the extrarenal distribution of
polycystins, encoded by PKD1 and PKD2 genes, ADPKD is a systemic disease, with
multiple extrarenal manifestations, including arterial hypertension, aneurysms,
and cysts in solid organs, like liver, pancreas, and spleen[1].
ADPKD is
well-known risk factor for intracranial aneurysms (IAs)[3]. The
frequency of IAs in ADPKD is increased compared to the general population, and
estimated to 4-22.5%[4,5]. Aneurysm formation is due to the
ciliopathy-related dysfunction of the vascular wall in a mechanism dependent on
downregulation of survivin expression[6]. The rupture of an IA is
associated with a high risk of serious complications or death[7,8].
The age of IA rupture is lower in ADPKD compared to the general population.
Additionally, ADPKD is connected to increased morbidity and mortality due to
the rupture of IA[9].
Despite these
facts, universal screening for IAs in ADPKD population remains controversial,
mainly due to the potential risk connected to pre-emptive treatment of IA, and
costs associated with screening[10]. However, to improve patients¡¯
outcomes, patients at risk for IA should be identified, screened, and
prophylactically treated if required. From the point of view of a nephrologist,
it is crucial to answer two questions: (1) which ADPKD patients should undergo screening
for IAs; and (2) how this screening should be done. The aim of the article is
to review the indications for screening as well as the methods of it based on
current literature on the subject.
INDICATIONS
FOR SCREENING FOR INTRACRANIAL ANEURYSMS
Family history
of intracranial aneurysm
IAs occur more frequently in ADPKD patients with a family history for
IA compared to those without a family history[11,12,13]. Therefore,
family history of IA is the main indisputable indication for screening for IA.
In general, all involved members of a family have the same type of mutation,
what suggest that the type of mutation correlates with a risk for IA. Then, an
ADPKD patient with a history of IA in a family member requires screening
regardless of the degree of kinship.
It was not
specified at which age the screening should be started in this group. However,
rupture of IA in ADPKD may occur even at a very young age[14,15].
Thus, it is rather not judicious to define a threshold age, below which the
screening is not recommended.
Also, a
patient with a past history of IA requires periodic follow-up for new IAs.
Neurological
symptoms
Symptoms suggestive of IA are considered an
indication for IA screening in ADPKD[16]. However, which symptoms
should be considered as suggestive of IA, remains controversial. While focal
neurological deficits are obvious indications for neurological assessment
including the possibility of IA, headache was questioned to be a symptom of IA[17].
Headache is observed in 15-49% of ADPKD patients[17,18], and may be
caused by other reasons, for example arterial hypertension, which is common in
ADPKD; up to 60% of young ADPKD patients with normal renal function are
hypertensive[19], and the overall prevalence of hypertension exceeds
80%[20]. On the other hand, in the general population, headache may
be a manifestation of IA; according to Lebedeva et al[21],
IAs are connected to increased frequency of migraine, and the remission of
migraine was observed after clipping of IA[22]. In my opinion, there
is no reason to think it is not a case in ADPKD patients. Indeed, according to
our small, retrospective analysis including ADPKD patients who passed a
non-fatal rupture of IA, half of them complained of headache in months
preceding the rupture[23]. Therefore, I believe that in ADPKD
patients reporting headache persisting after normalization of blood pressure,
screening for IA is judicious. Some other authors share my point of view[24].
Risk of sudden
loss of consciousness
According to guidelines[16], ADPKD patients with job or
hobby in which loss of consciousness may be lethal, should undergo screening
for IA. Obvious examples of such cases include airplane pilots, bus drivers,
paratroopers, and others. However, this indication leaves the field open to
interpretation, and eventually, this group may become very wide, as each person
with driving license meets this criterion.
Major elective
surgery
Due to the risk of IA rupture during surgery, screening is recommended
as a part of preparation for a major elective surgery[16]. However,
it has not been specified which procedures should be considered as ¡°major,¡± and
whether native nephrectomy, or renal transplantation belongs to this category.
It is important, as a large group of ADPKD patients after 50th
year-of-age develops ESRD, and they become candidates for renal transplantation
as a treatment of choice[25]. Additionally, 20% of them require
native nephrectomy before, or simultaneously with transplant procedure[26].
Moreover, ADPKD patients with ESRD have increased risk for a hemorrhagic stroke
compared to other ESRD reasons[27]. Although screening for IA is not
always considered a routine procedure before native nephrectomy, or renal
transplantation, it is increasingly performed in such cases. In some centers,
as much as 90% of ADPKD patients who underwent renal transplantation, had the
screening performed[28].
Extreme anxiety
of the patient regarding the risk of IA
When an ADPKD patient is extremely anxious of having IA, the screening
for it should be done[16]. The anxiety may be connected to, or
heightened by, the patients' knowlegde from non-medical sources, like for
example websites. However, it is difficult to clearly differentiate between
extreme and mild or moderate anxiety. Therefore, I feel it is reasonable to
screen each patient who expresses his, or her, anxiety.
Age
The occurrence if IAs increases with patients' age. In a Chinese study,
the prevalence of IAs in ADPKD increased after 30th year of age, reaching the
peak value between 60 and 69 years of age[12]. The increase in
prevalence of IAs was also reported in Caucasian ADPKD patients; however, it
started to increase after the age of 45 years[29]. Taking together
the increasing risk for IAs with age, and, mentioned above, the probability of
need for surgery in this patients, it should be a subject to discussion whether
the patient age should become an indication for screening for IAs in ADPKD.
Hypertension
Arterial hypertension (AH) is a risk factor for IAs in the general
population[30], but is not considered a risk factor for IAs in ADPKD[10].
In fact, the relative risk for IAs in ADPKD patients is higher compared to
patients with primary AH[31]. It is connected to the fact that IAs
in ADPKD are mainly due to the disease-specific dysfunction of the vascular
wall[6], and ADPKD-associated secondary hypertension is of
relatively low significance for the development of IAs. Therefore, the
diagnosis of AH, which is common in ADPKD[32], is not helpful in
selection of patients requiring screening for IAs. However, the dysfunction of
vascular wall belongs to main pathomechanisms of secondary AH in ADPKD[32].
Most probably that is why there are some links between development of IAs and
AH in ADPKD patients. In a study of Xu et al[12], occurrence
of IAs was correlated with the duration of AH. However, it is not easy to
employ this finding into the clinical practice, as precise estimation of the
duration of AH may be difficult due to the fact that AH may be asymptomatic,
and its diagnosis is often delayed. Additionally, in our study[33],
development of IAs positively correlated with some blood pressure parameters
measured with ambulatory blood pressure monitoring (ABPM). We suggested that
these associations may reflect the severity of the ciliopathy-related vascular
wall dysfunction, reflecting in both IA development, and the severity of AH.
However, further studies are needed to confirm our findings and to determine
levels of blood pressure parameters suggesting of IA development. Afterwards,
the ABPM software should be designed to automatic descry of these
abnormalities.
Future
perspectives
Clustering of IAs in families suggests that the type of mutation
correlates with the risk for IA development. According to the literature, IAs
occur in both types of the disease, but patients with type 1 are more likely to
develop vascular complication when they have a mutation to the 5' half of PKD1[34].
Therefore, with future progress in mutation screening it may be possible to
identify families at risk for IAs development[35]. Additionally, in
families with IAs without ADPKD, a number of genes/proteins that may reflect
the risk for IAs development were identified[34]. Similarly,
circulating microRNAs were proposed to be suggestive of IAs in patients without
ADPKD[36]. These potential markers need to be tested in ADPKD
patients to assess whether they may be helpful in selection of patients for
screening.
METHODS OF
SCREENING FOR INTRACRANIAL ANEURYSMS
The method of choice in detecting IAs in ADPKD is the magnetic
resonance angiography (MRA) due to the lack of X-ray exposure and no need for
contrast media administration[29]. In patients with
contraindications for MRA, including implanted electronic devices, or
ferromagnetic foreign bodies as the most important ones, computed tomography
angiography (CTA) should be implemented, as an alternative method. However, in
such cases, risk for contrast induced-acute kidney injury, especially in
patients with impaired renal function, must always be kept in mind, and
preventive measures have to be used. Positive results of MRA usually require
confirmation with CTA[29].
FINAL
REMARKS
The patient with IA detected on imaging should be referred to a
specialist in neurosurgery in order to decide whether the treatment is
required, and, if yes, when, and how (endovascularly or surgically) it should
be done. Due to the facts that the risk for enlargement and rupture of IA in
ADPKD is quite low and is not higher compared to the general population[13,37],
and, on the other hand, the rate of complications of IA treatment, at least
endovascular, is increased compared to the general population[4],
the decision on treatment must be deliberate, and only patients with high risk
for IA rupture should be treated. If the treatment is not conducted, the method
and timing of follow-up need to be determined.
Despite the
fact that the risk for development of new IAs is low[13], I feel it
is judicious to repeat the screening periodically, notwithstanding negative
result at the previous examination. While I do not propose any specific
intervals between MR imaging, I think that quinquennial seems reasonable.
Additional issue is that MRA has limited specificity, especially in detecting
very small IAs, which nota bene, have minimal risk for rupture. Therefore,
suspicion of an IA ¡Ü 2 mm in diameter should not be
verified with CTA, but may only require periodic follow-ups with MRA, and
should only be verified in case of enlargement. Again, there is no data to
support any specific intervals between successive examinations, but once a year
seems reasonable[29].
Data on
benefits of screening for IAs in ADPKD are suboptimal. Almost 2 decades ago,
Butler et al[38] presented results of a decision analysis
supporting routine screening with MRA. Seven years later, benefits of screening
ADPKD patients without a history of IA rupture were impeached[39].
There have been no literature data on the risk-benefit analysis of screening
for IAs in ADPKD from the last decade.
CONCLUSIONS
It is well known that ADPKD is a risk factor for IAs. Also, effective
methods for the diagnosis and treatment of IAs are available. Therefore, in the
21st century, it is hardly acceptable that there are still patients
who die or become disabled due to the rupture of an IA. Then, attempts to
develop a set of criteria for screening for IAs are worth of recognition.
However, current criteria are of suboptimal precision, and leave the field open
to interpretation. They need polishing, as according to some of them, the vast
majority of ADPKD patients should be screened, what I do not expect to be
widely acceptable. Additionally, in my opinion, what is also important in
prevention of IA rupture in ADPKD, is the awareness of patients and their
physicians, of the risk. Therefore, in addition to the efforts for optimization
of screening indications, education of both patients, and physicians, is
necessary.
CONFLICT OF INTERESTS
The author declare no conflict of interest.
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Po/ Castellana 261, 28046. Madrid. Spain.
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