The entire cohort’s patient characteristics are summarized in Table 1 and Online Resource 2. During baseline IA screening, the median age, eGFR, and TKV were 44 years, 54.5 mL/min/1.73 m2, and 1054.3 mL, respectively. A family IA/SAH history was confirmed in 94 (18.1%) patients, and 282 (54.3%) patients had hypertension. IA and SAH point prevalence among the 519 patients with ADPKD at baseline screening was 12.5% (65 patients) and 3.1% (16 patients), respectively. During a clinical follow-up of 3104 patient-years in these 519 patients, de novo IAs were detected in 29 patients (0.93% [95% confidence interval (CI), 0.62–1.34%] patient-years for saccular IAs), and three patients had IA rupture (0.10% [95% CI, 0.02–0.28%] patient-years). Accordingly, at the time of the last follow-up (median, 60 years), IA and SAH period prevalence among the 519 patients with ADPKD was 18.1% (94 patients) and 3.7% (19 patients), respectively.
Comparative analyses with and without IA revealed that the frequency of family IA/SAH history was higher among patients with IAs than among those without (28.7% vs. 15.8%, P=0.0032). Baseline hypertension (70.2% for patients with IA vs. 50.8% for those without, P=0.0006) was more frequent and the age was older (47.5 vs. 43 years, P=0.0052) in the aneurysm group. Regarding kidney findings during baseline IA screening, eGFR was significantly lower in patients with IA (35.2 mL/min/1.73 m2) than in those without (59.0 mL/min/1.73 m2; P<0.0001), and TKV was significantly higher in patients with IA than in those without (1459.0 mL with IA vs. 947.9 mL without IA; P<0.0001). The proportions of patients with chronic kidney disease (CKD) stages 3–5 (73.4% with IA vs. 51.3% without IA, P<0.0001) and those with Mayo imaging classification Class 1D–1E (38.0% with IA vs. 24.6% without IA, P=0.0154) were higher in the aneurysm group.
Characteristics of Patients with IAs
IA-associated patient and aneurysm characteristics are shown in Table 2. Ninety-four patients were diagnosed at a median age of 46 (range, 18–81) years, and 24 (25.5% of patients with IA) presented with multiple aneurysms. All IAs were small (maximum IA diameter <10 mm), with a median maximum IA diameter of 3.5 (range, 2.0–8.3) mm. The most frequent IA site was the middle cerebral artery in the anterior circulation. Nineteen patients (20.2%) experienced aneurysm rupture, and the median age at the time of rupture was 39 (range, 29–71) years. Treatment included neurosurgical procedures with IA clipping or coiling in 51 (54.3%) patients (clipping, 42 patients; coiling, nine patients).
IA/SAH and Risk-Factor Associations
First, we investigated the relationship between the progression of ADPKD-related factors and IA/SAH. Thus, risk factors for IA in the general population as well as ADPKD-related factors, including TKV (<1000 mL, 1000–1500 mL, and ≥1500 mL), height-adjusted TKV (htTKV) (<500 mL, 500–1000 mL, and ≥1000 mL), Mayo imaging classification (Classes 1A, 1B–1C, and 1D–1E), and CKD stages (1–2, 3, and 4–5), were examined using age-adjusted logistic regression analyses (Online Resource 3, Figure 2). As the TKV (Figure 2A–2B) and htTKV increased (Figure 2C–2D), and as the Mayo class (Figure 2E–2F) and CKD stage advanced (Figure 2G–2H), the odds ratios for IA/SAH increased.
Multivariable logistic regression analyses using the general risk factors for IA, as well as TKV, htTKV, Mayo classification, or CKD stage, were performed for IA formation (Table 3 and Online Resource 4, upper part). In the model using general risk factors for IA, hypertension (OR=2.58, P=0.0006) and family history of IA/SAH (OR=2.41, P=0.0013) were significantly associated with IA formation (McFadden’s pseudo-R2=0.06, AUC=0.66). Adding TKV to the model of general risk factors increased the AUC to 0.72 and the pseudo-R2 value to 0.11. The TKV (100 mL increase; OR=1.05, P<0.0001) was significantly associated with IA formation, indicating that adding TKV improved the model’s discriminatory ability and goodness-of-fit to predict IAs. Similarly, adding htTKV, Mayo 1D–1E, and eGFR to the model of general risk factors also increased the AUC (0.72, 0.71, and 0.70, respectively) and pseudo-R2 value (0.11, 0.10, and 0.08, respectively). The htTKV (100-mL increase; OR=1.09, P<0.0001), Mayo 1D–1E (OR=2.90, P=0.0012), and eGFR (10 mL/min/1.73 m2 decrease; OR=1.21, P=0.0004) were significantly associated with IA diagnosis. Therefore, adding htTKV, Mayo 1D–1E, and eGFR improved the model’s discriminatory ability and goodness-of-fit to predict IAs. Similarly, multivariable logistic regression analyses based on binary data confirmed ADPKD-related factors, including TKV ≥1000 mL (OR=2.81, P=0.0006), htTKV ≥500 mL (OR=2.81, P=0.0018), Mayo 1D–1E (OR=2.52, P=0.0037), and CKD stages 3–5 (OR=2.31, P=0.0062) to be significantly associated with IA formation (Table 3; Online Resource 4, lower part; Online Resource 5).
In the age-specific Kaplan–Meier model, which was based on the age at IA confirmation (Figure 3), the IA-free survival rates demonstrated no differences between men and women, especially before the age of 50 years (Figure 3A). In contrast, the IA-free survival rates in patients with a family history of IA/SAH and Mayo 1D–1E were significantly lower than those in patients without a family history of IA/SAH and without Mayo 1D–1E, even before the age of 50 years (Figure 3B–C; log-rank, P=0.00025, log-rank, P<0.0001, respectively).