Mutation Type and Intracranial Aneurysm Formation in Autosomal Dominant Polycystic Kidney Disease

Screening for intracranial aneurysms (IAs) in patients with risk factors of IA is recommended. However, genetic risk factors of IA in patients with autosomal dominant polycystic kidney disease (ADPKD) remain unclear, and genotype-phenotype relationships in IAs in patients with ADPKD have not been clarified. Therefore, we aimed to clarify the associations between germline mutations and IA formation in patients with ADPKD.

A total of 135 patients with ADPKD who were evaluated for ADPKD mutations were examined for IA formation in this single-center observational study.

The incidence of de novo IA formation was 1.3% per patient-year. Age at IA diagnosis was younger in patients with frameshift (median, 36 years; P=0.003) and splicing mutations (median, 43 years; P=0.046) than in patients with substitutions (median, 63 years). Multivariable analyses showed that IA was associated with female sex (odds ratio [OR], 3.32 [95% CI, 1.10-10.01]; P=0.03), a family history of IA or subarachnoid hemorrhage (OR, 3.05 [95% CI, 1.07-8.71]; P=0.04), estimated glomerular filtration rate (OR, 0.69 [95% CI, 0.54-0.87]; P=0.002), and splicing mutations (OR, 9.30 [95% CI, 1.71-50.44]; P=0.01). Splicing mutations showed a significant association with IA formation even in subcohorts with minimal risk factors for IA, such as age <50 years (OR, 19.52 [95% CI, 3.22-118.51]; P=0.001), nonhypertension (OR, 49.28 [95% CI, 3.60-673.98]; P=0.004), and nonsmoking behavior (OR, 27.79 [95% CI, 3.49-221.21]; P=0.002). Conversely, substitutions showed significant associations with IA formation in subcohorts such as age ≥50 years (OR, 8.66; 95% CI, 1.43-52.51; P=0.02) and chronic kidney disease stages 4 and 5 (OR, 10.70 [95% CI, 1.05-108.75]; P=0.045).

Genetic analyses in patients with ADPKD could contribute to IA screening and could be useful for evaluating the prognosis, including complications. IA screening should be recommended for patients with ADPKD who have splicing and frameshift mutations and for older patients or patients with advanced ADPKD who have substitutions.