Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is one of the relatively common genetic diseases affecting approximately one in 400 to 1,000 people worldwide. It is a genetic disease that invades the kidney parenchyma with multiple cysts and reduces kidney function [1]. It is known that mutations in the PKD1 and PKD2 genes are the cause of ADPKD [2]. The number and size of renal cysts increase as the disease progresses, and end-stage renal disease gradually progresses around age 60 [1,3]. It causes cystic formation in other organs, such as the pancreas and liver, and it is associated with arterial hypertension, which is clinically critical intracranial aneurysms (ICA). ICA is found in approximately 10% of ADPKD patients [1,2]. ICA is one of the most important diseases associated with ADPKD. The rupture of ICA and the occurrence of subarachnoid hemorrhage (SAH) are fatal to ADPKD patients [2]. According to a paper, it was announced that about 12% of patients with ADPKD had ICA when they received a diagnostic screening [3]. There is also a higher incidence rate of cerebral aneurysm rupture in younger patients than in patients with normal cerebral aneurysms, showing risk of serious complications and high mortality rate [4-6]. Compared to healthy patients, the prevalence of ICA is reported to be approximately three to four times higher in ADPKD patients. It is also reported that compared to healthy patients, ADPKD patients are five times more likely to develop SAH due to ICA rupture [5,6]. Thus, screening for rapid diagnosis is crucial for ADPKD patients. There are no clear guidelines regarding the natural history, risk factors, appropriate diagnosis, and treatment of ADPKD patients with ICA. The current American Heart Association/American Stroke Association guidelines recommend a noninvasive screening for all patients with ADPKD. The Kidney Disease Improving Global Outcomes conference also recommends a selective screening for patients with other risk factors [7,8]. According to the study by Butler et al. [9], diagnostic screening in ADPKD patients with ICA had a positive impact on the prognosis of patients and was also cost-effective. However, no specific guideline has been presented for the clear natural course, prognosis, and treatment strategy of ICA patients with ADPKD. This study is a retrospective study conducted for 10 years at a single institution on the ADPKD patients with ICA. It investigated the prognosis and characteristics of the treated and untreated groups among ICA patients with ADPKD. In addition, ICA patients who received treatment were divided into a ruptured group and a non-ruptured group to examine their characteristics and prognosis.

Methods

Ethical statements: This study was approved by the Institutional Review Board (IRB) of Kosin Medical Center (IRB No. KUGH IRB 2024-04-018-002). Written informed consent was waived.

The patient research was conducted by first selecting ADPKD patients and cross-checking the diagnostic codes of unruptured cerebral aneurysm, SAH, and ruptured aneurysm. This study conducted a survey for 10 years, from January 2013 to December 2022, and 33 patients were enrolled in the study. Of the 33 patients, 16 of them who did not receive treatment were excluded from this study, and all patients had unruptured cerebral aneurysms. Basic information included the age and sex of the patients, location and size of the cerebral aneurysm, and data on smoking, family history, and aneurysm treatment method.

Seventeen patients received either a conventional surgical treatment (clipping, trapping) or an endovascular interventional treatment (coiling, stent assisted coiling), and they were treated in the neurological intensive care unit. As the patient was an ADPKD patient with existing kidney lesions, special care was taken in the treatment. During the conventional surgery, all medications which may involve a strain on the kidneys were excluded, and special care was taken during the endovascular treatment. When performing transfemoral cerebral angiography (TFCA) and interventional cerebrovascular treatment (coiling) for the diagnosis of the ICA in patients, the following protocol was implemented before and after the procedure. In cases of TFCA or coiling that require the use of contrast medium, overnight hydration was performed using 2 L of normal saline fluid, and the same was performed after the procedure. In addition, N-acetylcysteine was taken before the procedure to minimize the kidney damage. In cases of patients with SAH caused by ICA rupture, sufficient hydration was performed using normal saline during the procedure or after the surgery since such a protocol was not able to be performed before the procedure.

The patient group was divided into two subgroups. The first group consisted of patients with SAH caused by ruptured ICA, and the second group consisted of patients with unruptured ICA. After dividing into two subgroups, data research was conducted on patient characteristics, treatment methods, and prognosis for each group. Then, statistical comparison tests were also conducted between the two groups. All patients included in the study were diagnosed with ADPKD prior to ICA diagnosis. In addition, in the group of patients who received a surgical treatment for SAH due to a ruptured aneurysm (six patients), no one previously had a diagnostic screening for cerebral blood vessels. In cases of patients with unruptured cerebral aneurysms, the patients were diagnosed by using computed tomography (CT) or magnetic resonance angiography (MRA), and all patients underwent TFCA. All patients with SAH were initially diagnosed with CT, and they also received TFCA additionally. Imaging follow-up of patients who received treatment was performed for 6 months to 1 year, and CT angiography or MRA were adopted as the diagnostic methods for follow-up observation. The prognosis of the patients who performed the study was confirmed 6 months after discharge.

The data used in this study were analyzed using SPSS 25.0 for windows (IBM Corp.). The mean values expressed as continuous variables were analyzed using Student t-test, and dichotomous variables were analyzed using Fisher exact test. All results with a probability value of less than 0.05 were considered statistically significant.

Results

Data was collected on patients at a single institution for a total of 10 years from January 2013 to December 2022. Among 33 ADPKD patients with ICA, 17 of them underwent conventional surgery or interventional endovascular procedures. According to data collection results, the mean age of ADPKD patients with ICA was 57.4 years, and 12 of them were females, accounting for 70.6% of the total patients. Three of the 17 patients had a smoking history. The mean size of cerebral aneurysm was 5.34±3.32 mm, and 64.7% of patients were aware of ADPKD at the time of first diagnosis of ICA. Among them, one patient had multiple ICAs, and two patients had a family history, which is one of the important past histories. Four patients received a clipping surgery, a conventional craniotomy, while the remaining 13 patients took an interventional endovascular treatment (coiling or stent assist coiling) (Table 1). A research was conducted by dividing patients into two subtypes: those in which SAH occurred due to ruptured cerebral aneurysm and those in which SAH did not occur. To examine the characteristics of each group, the location of the ICA was first examined (Table 2). Characteristically, bifurcation of middle cerebral artery was the most common location in both groups, and treatment of ICA located in the para-clinoid segment of the internal cerebral artery was found only in the non-ruptured group.

The results of the investigation into the characteristics of the SAH group are summarized in Table 3. Six patients were diagnosed with SAH and all patients received an emergency treatment within 24 hours and received an intensive care in the neurological intensive care unit. Four out of six patients with SAH had known ADPKD at the time of diagnosis. The locations of cerebral aneurysms were anterior circulation in four patients and posterior circulation (superior cerebellar artery, basilar artery) in two patients. The existence of ICA was unknown because all patients had not been screened previously. Two patients had a family history of cerebral aneurysm. Five patients were treated with the interventional endovascular method, and the remaining one patient underwent open surgery (clipping and decompressive craniectomy) case of a large amount of SAH and high intracranial pressure. Four of the treated patients were discharged without neurological deficits, and two of them remained with neurologic deficits. It was not a problem due to complications of surgery and treatment, but the level of consciousness was poor at the time of SAH diagnosis. Two patients were discharged with a Hunt-Hess grade (grade 4) which was the same as when they visited the emergency room at the institution, and there was no difference in their modified ranking scale scores during follow-up.

A total of 11 patients were enrolled, and all ICA locations were anterior circulation. Seven patients were aware of ADPKD at the time of diagnosis (63.6%). Eight patients were treated with an interventional endovascular method, and three patients underwent a conventional open surgery (72.7%). One of the patients who underwent open surgery was additionally treated with the endovascular method 5 years later due to regrowth of the aneurysm (Fig. 1). The difference from other patients was the size of the cerebral aneurysm. It was a large aneurysm (18 mm in size), and aneurysm clipping was selected as a treatment method due to concerns about recurrence caused by regrowth and coil compaction when treated with an endovascular treatment. Open surgery was performed for ICA of the left posterior communicating artery, surgical ligation was performed using a 20 mm straight clip. Meanwhile, TFCA was performed 5 years later as a follow-up. As a result, an ICA of about 15 mm regrew and was treated with stent-assist coiling (Table 4). In cases where SAH occurred due to ICA rupture, surgical clipping and decompressive craniotomy were required occasionally due to increased intracranial pressure. In these cases, even if the shape of the aneurysm is suitable for endovascular treatment, conventional surgical treatment is necessary (Fig. 2). In the other 10 patients, no recurrence of the treated aneurysm or new aneurysm was found elsewhere during the follow-up examination.

Of the 17 patients, 11 of them were unruptured patients, and the remaining six patients were ruptured patients with SAH (Table 5). The mean age values for unruptured and ruptured ICA were 58.8 years and 54.8 years, respectively (p=0.475). The mean size of the aneurysm was 5.8 mm in the unruptured cerebral aneurysm patient group and 4.4 mm in the SAH patient group, slightly larger in the former patient group, but not statistically significant (p=0.410). The remaining variables, including smoking, awareness of ADPKD at the time of aneurysm diagnosis, and family history of ICA, did not show statistically significant values. The location of the aneurysm (anterior circulation vs. posterior circulation) obtained a statistically significant value in the comparison between the two groups (p=0.041).

Discussion

The incidence of ICA in ADPKD patients has been reported to be approximately 10% to 12%, which is three times higher than that of the healthy population [4,5,8,9]. Rupture of the ICA is the cause of approximately 80% of spontaneous SAH. In ADPKD patients, ICA is the most common vascular-related complication. However, due to the lack of accurate and large studies of ADPKD patients with ICA, information regarding the incidence rate, natural history, and prognosis is lacking [1,3,5,6]. The ICA patients with ADPKD ruptured aneurysms at a younger age than other groups. Rupture of cerebral aneurysms has a lethal mortality rate and involves permanent neurological deficits [4-7]. The annual incidence rate of spontaneous SAH in the world population is approximately 0.01%. However, among patients with ADPKD, the incidence rate of SAH is about four times higher than that of the general population. As mentioned above, the probability of aneurysm rupture is higher at a younger age, and it is reported that rupture occurs in smaller aneurysms [10]. Therefore, appropriate diagnostic screening and surgical treatment are crucial.

The expression of cerebral aneurysms in ADPKD patients is related to mutations in the PKD1 and PKD2 genes [11]. It is known that mutations in these genes increase smooth muscle cell apoptosis, contributing to aneurysm formation, especially in patients with hypertension [12,13]. Conventionally, early screening of ICA patients with ADPKD has been limited [14]. Selective diagnostic screening is recommended only for high-risk patients, such as those with a previous history of ICA, family history of SAH, or a history of hypertension [15-17]. The reason for this selective screening was that a contrast agent was used for the diagnosis of ICA or an invasive TFCA test required. However, with the recent development of contrast-free MRI scans and the reduced risk of TFCA, early regular ICA testing is recommended [18,19]. As a result of this study, a total of 17 patients were treated for ICA, six of them who were treated after SAH had not been previously diagnosed with ADPKD. On the other hand, all but four out of 11 unruptured ICA treated patients were found through early screening. SAH due to rupture of a cerebral aneurysm may be fatal even if treated in the early stage. About one-third of SAH patients die, another one-third remain severely disabled, and only the remaining patients recover from the hemorrhage [20]. Furthermore, since rupture occurs in ICA at a younger age and at a smaller size than other general populations, early screening is considered necessary.

The treatment of ICA patients with ADPKD was mostly open surgery, that is, clipping. This is because there is a concern about renal toxicity as the endovascular treatment method itself uses an amount of contrast agent. However, the recent development of treatment methods for renal toxicity of contrast media, endovascular methods have become a good treatment option [21-23]. This study treated a total of 17 patients, 13 of whom were treated with endovascular methods. In the data, the clipping method was used when a decompressive craniotomy was required due to a large amount of SAH or when an additional stent was required in addition to the coiling in endovascular methods due to a wide neck of the aneurysm (Fig. 2). Endovascular treatment clearly has several advantages over the conventional clipping surgery. First, the treatment time is relatively short. In cases of end stage renal function state in ADPKD patients, if surgery is performed for a long time, there is a high possibility of problems occurring in other organs such as the lungs or heart of the patients [24,25]. Second, in cases of conventional clipping surgery, the level of difficulty varies depending on the location of the cerebral aneurysm. In cases of aneurysms located proximal to the intracerebral artery, the difficulty of clipping is high, which not only prolongs the surgical running time but also increases the risk of complications caused by the surgery [25,26]. Even in cases of aneurysms located in the posterior location, endovascular treatment is more advantageous [10,27,28].

Among all 17 patients included in this study, 13 patients treated with ICA using interventional endovascular methods did not show deterioration of their renal function. Sufficient hydration for at least 12 hours overnight was performed using normal saline, and after the procedure, hydration was performed similarly and N-acetylcysteine was taken. Immediately after surgery, the patients were monitored in the intensive care unit and consulted with the nephrology department. As a result, all 11 patients with unruptured ICA were discharged without any complications, and two out of six patients with SAH were discharged with neurological deficits. In these two patients, the prognosis did not worsen due to complications during surgery or during treatment. As shown in Table 3, the two patients with neurological deficits were in a poor state of consciousness at the time of diagnosis due to a large amount of SAH and increased intracranial pressure. For ADPKD patients, a treatment method tailored to the situation may be better than an unconditional clipping. As in this study, when surgical decompression is required due to high intracranial pressure or when an aneurysmal endovascular stenting is not absolutely necessary due to the wide neck of the aneurysm, interventional endovascular methods may also be a good treatment method. It is the most important to quickly detect ICA before renal failure progresses seriously, and screening the aneurysm through CT angiography or MRA may be remarkably helpful in the treatment of ADPKD patients.

This study has limitations in that it is a retrospective study conducted at a single institution with a small sample size. There were no studies of ICA patients with untreated ADPKD.

ADPKD patients showed a three to four times higher incidence rate of ICA compared to healthy people. Additionally, SAH due to rupture of the ICA also occurs at a young age and when the size of the aneurysm is smaller. Therefore, appropriate screening for early detection of ICA is essential. A careful approach through sufficient hydration, medication for kidney protection, collaboration with nephrologists, and intensive care is important, and through this protocol, endovascular treatment is also one of the treatment options for patients with ADPKD with ICA.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

All the work was done by JHP.

Fig. 1.

Coil embolization performed in patients with recurrence after clipping surgery. (A) On transfemoral cerebral angiography, an intracranial aneurysm (ICA) was observed in the left posterior communicating artery (white arrow). A clip, a trace of previous surgery, is also observed (black arrow). (B) After the stent-assist coiling operation was completed, the ICA was no longer filled with contrast medium, and total occlusion was observed (white arrow).

Fig. 2.

Decompressive craniotomy and clip surgery performed in patients with elevated intracranial pressure. (A) Subarachnoid hemorrhage and intracerebral hemorrhage are observed predominantly in the right cerebral hemisphere on brain computed tomography (CT). (B) A cerebral aneurysm was observed at the bifurcation of the right middle cerebral artery on CT angiography (white circle). (C) After surgery, clip shadows were observed on brain CT, and bone flaps were removed to reduce intracranial pressure (white arrow). (D) In postoperative CT angiography, a clip is observed in the ruptured cerebral aneurysm (white arrow).

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Figure & Data

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