https://orcid.org/0000-0003-1498-2132
ABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD) is associated with an increased risk for developing intracranial aneurysms (IAs). We aimed to evaluate the frequency of diagnosis of IAs in the cross-sectional, population-based, Genkyst cohort, to describe ADPKD-associated IAs and to analyse the risk factors associated with the occurrence of IAs in ADPKD patients.
A cross-sectional study was performed in 26 nephrology centres from the western part of France. All patients underwent genetic testing for PKD1/PKD2 and other cystogenes.
Among the 2449 Genkyst participants, 114 (4.65%) had a previous diagnosis of ruptured or unruptured IAs at inclusion, and ∼47% of them had a positive familial history for IAs. Most aneurysms were small and saccular and located in the anterior circulation; 26.3% of the patients had multiple IAs. The cumulative probabilities of a previous diagnosis of IAs were 3.9%, 6.2% and 8.1% at 50, 60 and 70 years, respectively. While this risk appeared to be similar in male and female individuals <50 years, after that age, the risk continued to increase more markedly in female patients, reaching 10.8% versus 5.4% at 70 years. The diagnosis rate of IAs was >2-fold higher in PKD1 compared with PKD2, with no influence of PKD1 mutation type or location. In multivariate analysis, female sex, hypertension <35 years, smoking and PKD1 genotype were associated with an increased risk for diagnosis of IAs.
This study presents epidemiological data reflecting real-life clinical practice. The increased risk for IAs in postmenopausal women suggests a possible protective role of oestrogen.
What is already known about this subject?
The most frequent and severe vascular feature in autosomal dominant polycystic kidney disease (ADPKD) is the development of intracranial aneurysm (IA).
IA prevalence is 5-fold higher in ADPKD than in the general population, with estimates ranging from 9% to 12%.
The only identified risk factor is the presence of a familial history of unruptured or ruptured IA.
What this study adds?
This study provides information about prevalence of detected IAs in one of the largest population-based cohorts of ADPKD patients. The cumulative probabilities of a previous diagnosis of IAs in the Genkyst cohort were 3.9%, 6.2% and 8.1% at 50, 60 and 70 years, respectively.
The risk of diagnosis of ruptured or unruptured IAs appears to be higher in women, especially after 50 years. This parallels observations made in the non-ADPKD population and suggests a possible protective role of oestrogens.
Multivariate analysis shows that female sex, age at diagnosis of hypertension <35 years, smoking exposure and PKD1 genotype are associated with an increased risk for diagnosis of IAs.
What impact this may have on practice or policy?
This study provides a real-life picture of diagnosis of IAs in ADPKD and may increase awareness and knowledge regarding prevalence and risk factors for IAs in ADPKD patients.
Policies regarding screening for IAs in ADPKD patients differ across countries and centres, and no clear recommendations have been made. Our study suggests that in at-risk women, screening probably should be repeated later in life than in men.
INTRODUCTION
Autosomal dominant polycystic kidney disease (ADPKD) affects ∼39–68 individuals in 10 000 [1, 2]. Mutations in PKD1 and PKD2, which encode polycystin 1 (PC1) and polycystin 2 (PC2), respectively, account for ∼75% and ∼18% of the ADPKD pedigrees [3]. Four other genes, GANAB, DNAJB11, ALG8 and ALG9, involved in protein biogenesis, have been more recently described in atypical forms of ADPKD and/or autosomal dominant polycystic liver disease [4–8].
In addition to the relentless development of renal and hepatic cysts, ADPKD is characterized by a wide spectrum of vascular complications, the most frequent and serious of which are intracranial aneurysms (IAs). In the non-ADPKD population, unruptured IAs are detected in 1.8–3.2% of the individuals screened by cerebral imaging, whereas the prevalence of IAs in ADPKD patients is nearly 5-fold higher, ranging from 9.3% to 12.4% when systematic screening strategies are employed [9–12]. IA rupture, leading to subarachnoid haemorrhage (SAH), is associated with significant morbidity and mortality and occurs ∼10 years earlier in the ADPKD population than in the general population, with respective median ages of 41 versus 51 years [13–15]. In the USA, the early mortality rate associated with SAH is estimated to be ∼20–30% [16–19]. Long-term complications of SAH include neurocognitive dysfunction, epilepsy and other focal neurologic deficits.
This susceptibility to IAs in ADPKD is thought to be mediated by a maladaptive response of the vascular wall to haemodynamic stress, resulting from defects in PC1 and PC2, which are abundantly expressed in vascular smooth muscle cells and the endothelium and likely act as pressure sensors [20–24]. Until now, the main risk factor identified for IA occurrence in ADPKD patients has been the presence of a positive personal or family history (FH) of unruptured or ruptured IAs, suggesting a predominant role of genetic determinants [9, 12]. Indeed, the prevalence of IAs is nearly four times higher in ADPKD patients with an FH of IAs (∼22%) than in those without such an FH (∼6%) [9, 12]. Previous studies in the early 2000s suggested an association of the localization of PKD1 mutations in the 5′ half of the gene with an increased risk for vascular complications [25]. However, PKD1 gene sequencing analysis is highly complex and was often incomplete at that time [26]. Compared with the general population, where non-modifiable (e.g. female sex) and modifiable risk factors (such as smoking, hypertension and possibly dyslipidaemia) are well identified, limited information is available in the ADPKD population [27–29].
Screening for IA using cerebral magnetic resonance imaging is currently recommended only for patients with an FH of IAs or SAH, patients with a high-risk profession (e.g. airline pilots) and patients who demand screening despite adequate information [30]. These recommendations relate to the cost associated with unnecessary screening and the risk of identifying IAs at low risk of rupture that are ineligible for treatment, causing anxiety to patients and their families. However, recent cost-effectiveness studies suggest a benefit of systematic screening strategies [31, 32]. It should be noted that the annual aneurysm rupture rates employed in these models were higher than those in other ADPKD cohorts [29].
This study aimed to evaluate the frequency of diagnosis of ruptured and unruptured IAs in the large population-based Genkyst ADPKD cohort, to describe ADPKD-associated IAs and to analyse the risk factors associated with the occurrence of IAs in ADPKD patients.
MATERIALS AND METHODS
Patients
This is a cross-sectional study involving 26 centres from the Genkyst Consortium in western France [33–35]. ADPKD patients >16 years of age were recruited from January 2010 to June 2019. ADPKD diagnosis was made by abdominal imaging, by employing the Pei criteria in the presence of a FH of ADPKD [36], or following the identification of a proven pathogenic PKD1 or PKD2 mutation. In the absence of FH or mutation identification, diagnosis required the presence of at least 10 bilateral kidney cysts. The patients’ clinical data obtained during medical interviews at the time of their inclusion and from medical records were entered into a standardized clinical report form (CRF). For participants in whom previous history of IAs was reported in the CRF, medical records were reviewed on study sites to confirm the previous history of IAs and to collect additional information regarding aneurysm size (in millimeters), type (saccular versus fusiform), localization (anterior or posterior circulation) and management (monitoring, neurosurgical or neuro-radiointerventional treatment). The screening strategy for detecting unruptured IAs was, in most cases, a targeted screening strategy, in accordance with the current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, i.e. by performing magnetic resonance imaging on patients with a positive FH of IAs, patients with at-risk occupations and patients requesting screening after comprehensive information. All participants provided informed consent, and the local ethics committee approved the study (CCTIRS 10.385).
Molecular analysis
All consenting patients underwent molecular genetic testing by Sanger sequencing for the PKD1 and PKD2 genes (patients included before March 2017) and/or targeted next-generation sequencing (NGS) of the PKD1, PKD2, GANAB, DNAJB11, HNF1B, PKHD1, SEC63, PKRKCSH and UMOD genes (patients included after March 2017 or before 2017 with no pathogenic variant detected by Sanger sequencing) in the Department of Molecular Genetics at Brest University Hospital, France. The latest version of the targeted NGS panel, in addition to the above-mentioned genes, also includes ALG8, ALG9, OFD1, COL4A1, DZIP1L, LRP5, PMM2, REN, SEC61B, SEC61A1, TSC1, TSC2 and VHL, and was used after September 2019 for reanalysis of genetically unresolved (GUR) patients. Patients with no clear pathogenic variant detected after Sanger sequencing or targeted NGS were screened for large rearrangements using the multiplex ligation-dependent probe amplification and array-based comparative genomic hybridization. Mutations were classified as truncating (frameshift, indels, nonsense mutations, canonical splicing changes and in-frame indels ≥5 amino acids) or nontruncating (missense, in-frame ≤4 amino acids and non-canonical splicing events).
Statistical analyses
Statistical analyses were performed using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, NY, USA). The frequency of IAs detected in our cohort was estimated and reported with a 95% confidence interval (CI) constructed for the estimate. Baseline data are expressed as the median and standard deviation or range. Quantitative data were compared using the non-parametric Mann–Whitney test or the Kruskal–Wallis test, depending on the number of groups. Qualitative data were compared using a t-test or the chi-squared test.
Survival without a diagnosis of IA and survival without ruptured IAs were analysed using the Kaplan–Meier method. The differences between the survival curves were assessed using a log-rank test with a 0.05 significance level.
Univariate Cox proportional hazards regression analysis was used to identify variables associated with IA diagnosis. Variables were entered into the Cox multivariate analysis when they were associated with ruptured or unruptured IA diagnosis in the univariate analysis at a conservative threshold of 20%. Complete observations were entered into the Cox multivariate analysis.
RESULTS
Baseline clinical parameters in the Genkyst cohort and genetic analyses
A total of 2449 ADPKD patients (1185 males) from 1810 pedigrees were included. The median age at inclusion was 55.1 years (range 16.2–94.3). The characteristics of the patients at inclusion are presented in Table 1. The results of genetic analysis were available in 2386 patients. PKD1 pathogenic variants were identified in 67.6% of the participants [n = 1612: truncating variants 44.1% (n = 1052) and non-truncating variants 23.5% (n = 560)], while PKD2 pathogenic variants were identified in 19% (n = 454). In 11.8% of cases (n = 281), no mutation was identified. Genetic analysis led to a differential diagnosis in 1.6% of the cases [n = 39: GANAB (n = 4), DNAJB11 (n = 5), HNF1B (n = 8), PKHD1 (n = 1), SEC63 (n = 2), PRKCSH (n = 3), OFD1 (n = 4), UMOD (n = 2), ALG8 (n = 6), ALG9 (n = 1), COL4A4 (n = 2) and COL4A1 (n = 1)].
Clinical characteristics of the study participants at inclusion or at diagnosis of IA
| Past history of IAsb | |||||
|---|---|---|---|---|---|
| Variable | Total cohorta | No past history of IAsa | All IAs | Unruptured IAs | Ruptured IAs |
| Patients (number of pedigrees), n (n) | 2449 (1810) | 2335 | 114 | 66 | 48 |
| Male | 1185 (48.4%) | 1141 (48.9%) | 44 (35.6%) | 27 (40.9%) | 17 (35.4%) |
| Median age (years)a,b | 55.1 (16.2–94.3) | 55.2 (16.2–94.3) | 48 (40.8–54.3) | 49 (45–57) | 43.5 (35.5–52.6) |
| CKD stagesa,b,c | |||||
| 1 2 3a 3b 4 5 Requiring RRT Missing | 456 (18.9%) 394 (16.3%) 236 (9.8%) 256 (10.6%) 211 (8.8%) 859 (35.6%) 762 (31.6%) 37a | 447 (19.4%) 384 (16.7%) 230 (10%) 247 (10.7%) 198 (8.6%) 793 (34.5%) 700 (30.4%) 36a | 20 (21.3%) 21 (22.3%) 7 (7.4%) 15 (16%) 15 (16%) 16 (17%) 9 (9.6%) 20b | 8 (13.3%) 10 (16.7%) 4 (6.7%) 11 (18.3%) 11 (18.3%) 16 (26.7%) 9 (15%) 6b | 12 (35.3%) 11 (32.4%) 3 (8.8%) 4 (11.8%) 4 (11.8%) 0 0 14b |
| Hypertension | |||||
| Yes No Missing | 1873 (77%) 559 (23%) 17 | 1763 (76.1%) 555 (23.9%) 17 | 110 (96.5%) 4 (3.5%) 0 | 64 (97%) 2 (3%) 0 | 46 (95.8%) 2 (4.2%) 0 |
| Hypertension before 35 years | |||||
| Yes No Missing NA | 535 (27.8%) 1390 (72.2%) 326 198 | 493 (27.2%) 1320 (72.8%) 325 197 | 42 (37.5%) 70 (62.5%) 1 1 | 29 (43.9%) 37 (56.1%) 0 0 | 13 (28.3%) 33 (71.7%) 1 1 |
| Smoking status | |||||
| Never smoker Past or active, <20 PY Past or active, >20 PY Missing | 1275 (56%) 799 (35%) 207 (9%) 168 | 1215 (56%) 763 (35.2%) 190 (8.8%) 167 | 60 (53.1%) 36 (31.9%) 17 (15%) 1 | 35 (53%) 24 (36.4%) 7 (10.6%) 0 | 25 (53.2%) 12 (25.5%) 10 (21.3%) 1 |
| FH of IAs | |||||
| No Yes | 2150 (87.8%) 299 (12.2%) | 2090 (89.5%) 245 (10.5%) | 60 (52.6%) 54 (47.4%) | 31 (53%) 35 (47%) | 19 (39.6%) 29 (60.4%) |
| Genotype | |||||
| PKD1 Truncating Non-truncating PKD2 Unresolved Other genes Missing | 1612 (67.6%) 1052 (44.1%) 560 (23.5%) 454 (19%) 281 (11.8%) 39 (1.6%) 63 | 1524 (63.8%) 997 (41.8%) 527 (22.1%) 442 (18.5%) 269 (11.3%) 39 (1.6%) 61 | 88 (77.2%) 55 (48.2%) 33 (28.9%) 12 (10.5%) 12 (10.5%) 2 (1.8%) 0 | 50 (75.8%) 34 (51.5%) 16 (24.2%) 10 (15.2%) 6 (9.1%) 0 0 | 38 (82.6%) 21 (45.7%) 17 (37%) 2 (4.3%) 6 (13%) 0 2 |
| Past history of IAsb | |||||
|---|---|---|---|---|---|
| Variable | Total cohorta | No past history of IAsa | All IAs | Unruptured IAs | Ruptured IAs |
| Patients (number of pedigrees), n (n) | 2449 (1810) | 2335 | 114 | 66 | 48 |
| Male | 1185 (48.4%) | 1141 (48.9%) | 44 (35.6%) | 27 (40.9%) | 17 (35.4%) |
| Median age (years)a,b | 55.1 (16.2–94.3) | 55.2 (16.2–94.3) | 48 (40.8–54.3) | 49 (45–57) | 43.5 (35.5–52.6) |
| CKD stagesa,b,c | |||||
| 1 2 3a 3b 4 5 Requiring RRT Missing | 456 (18.9%) 394 (16.3%) 236 (9.8%) 256 (10.6%) 211 (8.8%) 859 (35.6%) 762 (31.6%) 37a | 447 (19.4%) 384 (16.7%) 230 (10%) 247 (10.7%) 198 (8.6%) 793 (34.5%) 700 (30.4%) 36a | 20 (21.3%) 21 (22.3%) 7 (7.4%) 15 (16%) 15 (16%) 16 (17%) 9 (9.6%) 20b | 8 (13.3%) 10 (16.7%) 4 (6.7%) 11 (18.3%) 11 (18.3%) 16 (26.7%) 9 (15%) 6b | 12 (35.3%) 11 (32.4%) 3 (8.8%) 4 (11.8%) 4 (11.8%) 0 0 14b |
| Hypertension | |||||
| Yes No Missing | 1873 (77%) 559 (23%) 17 | 1763 (76.1%) 555 (23.9%) 17 | 110 (96.5%) 4 (3.5%) 0 | 64 (97%) 2 (3%) 0 | 46 (95.8%) 2 (4.2%) 0 |
| Hypertension before 35 years | |||||
| Yes No Missing NA | 535 (27.8%) 1390 (72.2%) 326 198 | 493 (27.2%) 1320 (72.8%) 325 197 | 42 (37.5%) 70 (62.5%) 1 1 | 29 (43.9%) 37 (56.1%) 0 0 | 13 (28.3%) 33 (71.7%) 1 1 |
| Smoking status | |||||
| Never smoker Past or active, <20 PY Past or active, >20 PY Missing | 1275 (56%) 799 (35%) 207 (9%) 168 | 1215 (56%) 763 (35.2%) 190 (8.8%) 167 | 60 (53.1%) 36 (31.9%) 17 (15%) 1 | 35 (53%) 24 (36.4%) 7 (10.6%) 0 | 25 (53.2%) 12 (25.5%) 10 (21.3%) 1 |
| FH of IAs | |||||
| No Yes | 2150 (87.8%) 299 (12.2%) | 2090 (89.5%) 245 (10.5%) | 60 (52.6%) 54 (47.4%) | 31 (53%) 35 (47%) | 19 (39.6%) 29 (60.4%) |
| Genotype | |||||
| PKD1 Truncating Non-truncating PKD2 Unresolved Other genes Missing | 1612 (67.6%) 1052 (44.1%) 560 (23.5%) 454 (19%) 281 (11.8%) 39 (1.6%) 63 | 1524 (63.8%) 997 (41.8%) 527 (22.1%) 442 (18.5%) 269 (11.3%) 39 (1.6%) 61 | 88 (77.2%) 55 (48.2%) 33 (28.9%) 12 (10.5%) 12 (10.5%) 2 (1.8%) 0 | 50 (75.8%) 34 (51.5%) 16 (24.2%) 10 (15.2%) 6 (9.1%) 0 0 | 38 (82.6%) 21 (45.7%) 17 (37%) 2 (4.3%) 6 (13%) 0 2 |
Values for categorical variables are given as number (%), and for continuous variables, as median (interquartile range). Abbreviations: NA, not applicable (corresponding to individuals <35 years with no hypertension).
aData at inclusion in the Genkyst cohort.
bData at diagnosis of IA.
cAccording to the estimated glomerular filtration rate (calculated using the CKD Epidemiology Collaboration creatinine equation).
Clinical characteristics of the study participants at inclusion or at diagnosis of IA
| Past history of IAsb | |||||
|---|---|---|---|---|---|
| Variable | Total cohorta | No past history of IAsa | All IAs | Unruptured IAs | Ruptured IAs |
| Patients (number of pedigrees), n (n) | 2449 (1810) | 2335 | 114 | 66 | 48 |
| Male | 1185 (48.4%) | 1141 (48.9%) | 44 (35.6%) | 27 (40.9%) | 17 (35.4%) |
| Median age (years)a,b | 55.1 (16.2–94.3) | 55.2 (16.2–94.3) | 48 (40.8–54.3) | 49 (45–57) | 43.5 (35.5–52.6) |
| CKD stagesa,b,c | |||||
| 1 2 3a 3b 4 5 Requiring RRT Missing | 456 (18.9%) 394 (16.3%) 236 (9.8%) 256 (10.6%) 211 (8.8%) 859 (35.6%) 762 (31.6%) 37a | 447 (19.4%) 384 (16.7%) 230 (10%) 247 (10.7%) 198 (8.6%) 793 (34.5%) 700 (30.4%) 36a | 20 (21.3%) 21 (22.3%) 7 (7.4%) 15 (16%) 15 (16%) 16 (17%) 9 (9.6%) 20b | 8 (13.3%) 10 (16.7%) 4 (6.7%) 11 (18.3%) 11 (18.3%) 16 (26.7%) 9 (15%) 6b | 12 (35.3%) 11 (32.4%) 3 (8.8%) 4 (11.8%) 4 (11.8%) 0 0 14b |
| Hypertension | |||||
| Yes No Missing | 1873 (77%) 559 (23%) 17 | 1763 (76.1%) 555 (23.9%) 17 | 110 (96.5%) 4 (3.5%) 0 | 64 (97%) 2 (3%) 0 | 46 (95.8%) 2 (4.2%) 0 |
| Hypertension before 35 years | |||||
| Yes No Missing NA | 535 (27.8%) 1390 (72.2%) 326 198 | 493 (27.2%) 1320 (72.8%) 325 197 | 42 (37.5%) 70 (62.5%) 1 1 | 29 (43.9%) 37 (56.1%) 0 0 | 13 (28.3%) 33 (71.7%) 1 1 |
| Smoking status | |||||
| Never smoker Past or active, <20 PY Past or active, >20 PY Missing | 1275 (56%) 799 (35%) 207 (9%) 168 | 1215 (56%) 763 (35.2%) 190 (8.8%) 167 | 60 (53.1%) 36 (31.9%) 17 (15%) 1 | 35 (53%) 24 (36.4%) 7 (10.6%) 0 | 25 (53.2%) 12 (25.5%) 10 (21.3%) 1 |
| FH of IAs | |||||
| No Yes | 2150 (87.8%) 299 (12.2%) | 2090 (89.5%) 245 (10.5%) | 60 (52.6%) 54 (47.4%) | 31 (53%) 35 (47%) | 19 (39.6%) 29 (60.4%) |
| Genotype | |||||
| PKD1 Truncating Non-truncating PKD2 Unresolved Other genes Missing | 1612 (67.6%) 1052 (44.1%) 560 (23.5%) 454 (19%) 281 (11.8%) 39 (1.6%) 63 | 1524 (63.8%) 997 (41.8%) 527 (22.1%) 442 (18.5%) 269 (11.3%) 39 (1.6%) 61 | 88 (77.2%) 55 (48.2%) 33 (28.9%) 12 (10.5%) 12 (10.5%) 2 (1.8%) 0 | 50 (75.8%) 34 (51.5%) 16 (24.2%) 10 (15.2%) 6 (9.1%) 0 0 | 38 (82.6%) 21 (45.7%) 17 (37%) 2 (4.3%) 6 (13%) 0 2 |
| Past history of IAsb | |||||
|---|---|---|---|---|---|
| Variable | Total cohorta | No past history of IAsa | All IAs | Unruptured IAs | Ruptured IAs |
| Patients (number of pedigrees), n (n) | 2449 (1810) | 2335 | 114 | 66 | 48 |
| Male | 1185 (48.4%) | 1141 (48.9%) | 44 (35.6%) | 27 (40.9%) | 17 (35.4%) |
| Median age (years)a,b | 55.1 (16.2–94.3) | 55.2 (16.2–94.3) | 48 (40.8–54.3) | 49 (45–57) | 43.5 (35.5–52.6) |
| CKD stagesa,b,c | |||||
| 1 2 3a 3b 4 5 Requiring RRT Missing | 456 (18.9%) 394 (16.3%) 236 (9.8%) 256 (10.6%) 211 (8.8%) 859 (35.6%) 762 (31.6%) 37a | 447 (19.4%) 384 (16.7%) 230 (10%) 247 (10.7%) 198 (8.6%) 793 (34.5%) 700 (30.4%) 36a | 20 (21.3%) 21 (22.3%) 7 (7.4%) 15 (16%) 15 (16%) 16 (17%) 9 (9.6%) 20b | 8 (13.3%) 10 (16.7%) 4 (6.7%) 11 (18.3%) 11 (18.3%) 16 (26.7%) 9 (15%) 6b | 12 (35.3%) 11 (32.4%) 3 (8.8%) 4 (11.8%) 4 (11.8%) 0 0 14b |
| Hypertension | |||||
| Yes No Missing | 1873 (77%) 559 (23%) 17 | 1763 (76.1%) 555 (23.9%) 17 | 110 (96.5%) 4 (3.5%) 0 | 64 (97%) 2 (3%) 0 | 46 (95.8%) 2 (4.2%) 0 |
| Hypertension before 35 years | |||||
| Yes No Missing NA | 535 (27.8%) 1390 (72.2%) 326 198 | 493 (27.2%) 1320 (72.8%) 325 197 | 42 (37.5%) 70 (62.5%) 1 1 | 29 (43.9%) 37 (56.1%) 0 0 | 13 (28.3%) 33 (71.7%) 1 1 |
| Smoking status | |||||
| Never smoker Past or active, <20 PY Past or active, >20 PY Missing | 1275 (56%) 799 (35%) 207 (9%) 168 | 1215 (56%) 763 (35.2%) 190 (8.8%) 167 | 60 (53.1%) 36 (31.9%) 17 (15%) 1 | 35 (53%) 24 (36.4%) 7 (10.6%) 0 | 25 (53.2%) 12 (25.5%) 10 (21.3%) 1 |
| FH of IAs | |||||
| No Yes | 2150 (87.8%) 299 (12.2%) | 2090 (89.5%) 245 (10.5%) | 60 (52.6%) 54 (47.4%) | 31 (53%) 35 (47%) | 19 (39.6%) 29 (60.4%) |
| Genotype | |||||
| PKD1 Truncating Non-truncating PKD2 Unresolved Other genes Missing | 1612 (67.6%) 1052 (44.1%) 560 (23.5%) 454 (19%) 281 (11.8%) 39 (1.6%) 63 | 1524 (63.8%) 997 (41.8%) 527 (22.1%) 442 (18.5%) 269 (11.3%) 39 (1.6%) 61 | 88 (77.2%) 55 (48.2%) 33 (28.9%) 12 (10.5%) 12 (10.5%) 2 (1.8%) 0 | 50 (75.8%) 34 (51.5%) 16 (24.2%) 10 (15.2%) 6 (9.1%) 0 0 | 38 (82.6%) 21 (45.7%) 17 (37%) 2 (4.3%) 6 (13%) 0 2 |
Values for categorical variables are given as number (%), and for continuous variables, as median (interquartile range). Abbreviations: NA, not applicable (corresponding to individuals <35 years with no hypertension).
aData at inclusion in the Genkyst cohort.
bData at diagnosis of IA.
cAccording to the estimated glomerular filtration rate (calculated using the CKD Epidemiology Collaboration creatinine equation).
Diagnosis of ruptured or unruptured IA
A total of 114 patients from 107 pedigrees had a previous diagnosis of ruptured or unruptured IAs (4.65%, 95% CI 3.56–5.74) (Figure1). A first diagnosis of IA was made at the time of IA rupture in 48 individuals, at the median age of 43.5 years (range 21–69), while unruptured IAs were detected in 66 individuals, at the median age of 49 years (range 24–78), leading to subsequent neurosurgical or neuro-radiointerventional treatment in 34 of them. Pre-symptomatic screening was mostly performed by magnetic resonance angiography (MRA), with a diagnosis of unruptured IA made by an MRA in 55 patients and by computed tomography angiography in 11 patients. The reasons for screening included a positive FH of IAs (n = 32, 48.5%), atypical headaches (n = 16, 24.2%), systematic screening despite a negative FH (n = 14, 21.2%) and evaluation before kidney transplantation (n = 4, 6.1%).
Flow diagram summarizing the diagnosis of ruptured and unruptured IAs in the Genkyst cohort.
The cumulative probability of diagnosis of ruptured or unruptured IAs was 1.3% at 40 years (95% CI 0.9–1.7), 3.9% at 50 years (95% CI 2.9–4.9) and 6.2% at 60 years (95% CI 5–7.4), and reached 8.1% at 70 years (95% CI 6.5–9.7) (Figure2A). The cumulative probability of diagnosis of ruptured aneurysm was 0.9% at 40 years (95% CI 0.5–1.3), 1.8% at 50 years (95% CI 1.2–2.4), 2.6% at 60 years (95% CI 1.8–3.4) and 3.2% at 70 years (95% CI 2.2–4.2) (Figure2B).
Cumulative probabilities of diagnosis of IAs and ruptured IAs. (A) Kaplan survival curve representing the cumulative probability of diagnosis of ruptured or unruptured IAs in the Genkyst cohort. The cumulative probability of diagnosis of IA is 3.9% at 50 years, 6.2% at 60 years and reaches 8.1% at 70 years. (B) Kaplan survival curve representing the cumulative probability of diagnosis of ruptured IA in the Genkyst cohort, which remains inferior to 4% at 70 years.
Patients with IA were more frequently female patients (61.4% versus 51.1%; P = 0.013), of PKD1 genotype (77.2% versus 63.8%; P = 0.001) and those being treated for hypertension (96.5% versus 76.1%; P = 0.007). Although non-significant, there were more smokers with exposure >20 pack-years (PYs) in the IA group than in the non-IA group (15% versus 8.8%; P = 0.095) (Table 1). IAs were diagnosed at all chronic kidney disease (CKD) stages. The FH of IAs was positive in 47.4% of the individuals with a diagnosis of ruptured or unruptured IAs.
Imaging characteristics of the aneurysms
A total of 159 IAs were detected in 114 patients. Multiple aneurysms were found in 30 patients, diagnosed either simultaneously (n = 16) or successively (i.e. recurrent diagnoses of different IAs, prior to inclusion in the Genkyst cohort) (n = 14). Amongst these 30 patients, 22 had two IAs, 3 had three IAs, 3 had four IAs and 2 had five IAs. A large majority of the 159 aneurysms were saccular (∼98%), and originated from the anterior circulation (89.3%) (Table 2). Size was available for 104/159 IAs (size was missing for 31 IAs diagnosed at rupture and 24 unruptured IAs, mostly diagnosed before 2000). Most of these IAs were small, measuring <7 mm (n = 85, 81.2%), including 47 IAs measuring <3 mm (45.2%). Only five patients were diagnosed with giant IAs (e.g. >10 mm, 3.6%). Of the 62 ruptured IAs in 48 patients, 49 were in the anterior circulation (87.5%), and 25 were <7 mm.
Characteristics of 159 IAs in 114 patientsa
| Characteristics | All aneurysms N = 159 | Unruptured aneurysms N = 97 | Ruptured aneurysms N = 62 |
|---|---|---|---|
| Type Saccular Fusiform Missing | 149 (98%) 3 (2%) 7 | 93 (96.9%) 3 (3.1%) 1 | 56 (100%) 0 6 |
| Location Anterior circulation Internal carotid artery Middle cerebral artery Anterior communicating artery Posterior communicating artery Posterior circulation Missing | 135 (90%) 21 74 39 1 15 (10%) 9 | 86 (91.5%) 13 51 22 0 9 (8.5%) 3 | 49 (87.5%) 8 23 17 1 7 (12.5%) 6 |
| Size <7 mm <3 mm ≥7 mm >10 mm Missing | 85 (81.2%) 47 19 (18.3%) 5 55 | 60 (82.2%) 31 13 (17.8%) 3 24 | 25 (80.6%) 16 6 (19.4%) 2 31 |
| Characteristics | All aneurysms N = 159 | Unruptured aneurysms N = 97 | Ruptured aneurysms N = 62 |
|---|---|---|---|
| Type Saccular Fusiform Missing | 149 (98%) 3 (2%) 7 | 93 (96.9%) 3 (3.1%) 1 | 56 (100%) 0 6 |
| Location Anterior circulation Internal carotid artery Middle cerebral artery Anterior communicating artery Posterior communicating artery Posterior circulation Missing | 135 (90%) 21 74 39 1 15 (10%) 9 | 86 (91.5%) 13 51 22 0 9 (8.5%) 3 | 49 (87.5%) 8 23 17 1 7 (12.5%) 6 |
| Size <7 mm <3 mm ≥7 mm >10 mm Missing | 85 (81.2%) 47 19 (18.3%) 5 55 | 60 (82.2%) 31 13 (17.8%) 3 24 | 25 (80.6%) 16 6 (19.4%) 2 31 |
aA toatal of 30 patients (26.3%) had >1 IA, either diagnosed simultaneously (n = 16) or diagnosed successively (de novo formation of IA) prior to inclusion in the Genkyst cohort (n = 14).
Characteristics of 159 IAs in 114 patientsa
| Characteristics | All aneurysms N = 159 | Unruptured aneurysms N = 97 | Ruptured aneurysms N = 62 |
|---|---|---|---|
| Type Saccular Fusiform Missing | 149 (98%) 3 (2%) 7 | 93 (96.9%) 3 (3.1%) 1 | 56 (100%) 0 6 |
| Location Anterior circulation Internal carotid artery Middle cerebral artery Anterior communicating artery Posterior communicating artery Posterior circulation Missing | 135 (90%) 21 74 39 1 15 (10%) 9 | 86 (91.5%) 13 51 22 0 9 (8.5%) 3 | 49 (87.5%) 8 23 17 1 7 (12.5%) 6 |
| Size <7 mm <3 mm ≥7 mm >10 mm Missing | 85 (81.2%) 47 19 (18.3%) 5 55 | 60 (82.2%) 31 13 (17.8%) 3 24 | 25 (80.6%) 16 6 (19.4%) 2 31 |
| Characteristics | All aneurysms N = 159 | Unruptured aneurysms N = 97 | Ruptured aneurysms N = 62 |
|---|---|---|---|
| Type Saccular Fusiform Missing | 149 (98%) 3 (2%) 7 | 93 (96.9%) 3 (3.1%) 1 | 56 (100%) 0 6 |
| Location Anterior circulation Internal carotid artery Middle cerebral artery Anterior communicating artery Posterior communicating artery Posterior circulation Missing | 135 (90%) 21 74 39 1 15 (10%) 9 | 86 (91.5%) 13 51 22 0 9 (8.5%) 3 | 49 (87.5%) 8 23 17 1 7 (12.5%) 6 |
| Size <7 mm <3 mm ≥7 mm >10 mm Missing | 85 (81.2%) 47 19 (18.3%) 5 55 | 60 (82.2%) 31 13 (17.8%) 3 24 | 25 (80.6%) 16 6 (19.4%) 2 31 |
aA toatal of 30 patients (26.3%) had >1 IA, either diagnosed simultaneously (n = 16) or diagnosed successively (de novo formation of IA) prior to inclusion in the Genkyst cohort (n = 14).
Sex and diagnosis of IA
The diagnosis rates of ruptured and unruptured IAs were 3.71% and 5.54% in male (n = 44) and female (n = 70) patients, respectively. The cumulative probability of diagnosis of ruptured or unruptured IAs was higher in female patients (P = 0.012, Figure3A). Interestingly, while cumulative probabilities for IA diagnosis appeared to be similar in individuals <50 years, after 50 years, probabilities continued to increase more markedly in female than in male patients. The cumulative probabilities of IAs in male and female patients were hence 1.2% (95% CI 0.6–1.8) versus 1.4% (95% CI 0.6–2.2) at age 40, 3.6% (95% CI 2.4–4.8) versus 4.2% (95% CI 2.8–5.6) at age 50, 5.1% (95% CI 3.5–6.7) versus 7.3% (95% CI 5.3–9.3) at age 60 and 5.4% (95% CI 3.8–7) versus 10.8% (95% CI 8–13.6) at age 70. The cumulative probability of diagnosis of ruptured IAs was also higher in the female group (P = 0.041): 3.2% (95% CI 2–4.4) versus 1.9% (95% CI 0.9–2.9) at age 60 and 4.5% (95% CI 2.7–6.3) versus 1.9% (95% CI 0.9–2.9) at age 70 (Figure3B).
Higher probability of diagnosis of unruptured and ruptured IA in female patients and in PKD1 patients. (A) Kaplan–Meier curves representing the cumulative probability of diagnosis of IAs in male and female patients. At age 60 years, cumulative probabilities of IA are 7.1% and 5.3% in female versus male patients, respectively. (B) Kaplan–Meier curves representing the cumulative probability of diagnosis of ruptured IAs in female versus male patients. At age 60 years, cumulative probabilities of ruptured IAs are 7.1% and 5.3% in female versus male patients, respectively. (C) Kaplan–Meier curves representing the cumulative probability of diagnosis of IAs in PKD1, PKD2 and genetically unresolved (GUR) ADPKD patients. At age 50 years, cumulative probabilities of IAs are 4.9% and 1.9% in PKD1 versus PKD2 patients, respectively. (D) Kaplan–Meier curves representing the cumulative probability of diagnosis of ruptured IAs in PKD1, PKD2 and GUR ADPKD patients. At age 50 years, cumulative probabilities of ruptured IAs are 1.9% versus 0.3% in PKD1 versus PKD2 patients, respectively.
Genotype of patients with IA
The respective diagnosis rates of ruptured or unruptured IAs were 5.46% and 2.64% in PKD1 (n = 88/1612) and PKD2 (n = 12/454) mutation carriers, respectively. No cases of IAs were reported in patients with GANAB (n = 4) or DNAJB11 (n = 5) mutations or patients harbouring pathogenic mutations in other genes screened on the panel (n = 30). The cumulative probability of diagnosis of ruptured or unruptured IAs was higher in PKD1 mutation carriers (P = 0.001; Figure3C and D). The cumulative probabilities of IAs in PKD1 and PKD2 mutation carriers were indeed 1.7% (95% CI, 1.4–2) versus 0.5% (95% CI 0.2–0.8) at age 40, 4.9% (95% CI 3.6–4.8) versus 1.9% (95% CI 1.2–2.8) at age 50 and 8.1% (95% CI, 7.2–9) versus 2.8% (95% CI 1.1–3.8) at age 60 (Figure3C). The cumulative probabilities of diagnosis of ruptured IAs were also significantly higher in the PKD1 group (P = 0.008), reaching 3.6% (95% CI 3–4.3) versus 0.7% (95% CI 0.2–1.2) at age 60 (Figure3D).
The distribution of PKD1 mutations along the PKD1 gene did not differ in patients with and without IAs, and the median amino acid position did not differ between groups (P = 0.057) (Figure4). We did not observe recurring mutations of PKD1 or PKD2 among unrelated individuals with IAs. Furthermore, there was no association between PKD1 mutation type (truncating versus non-truncating) and IA occurrence (P = 0.957) (Table 3).
Distribution of mutations identified along the PKD1 gene in each of the three groups: no known IAs, all IAs, unruptured IAs and ruptured IAs. The different PKD1 pathogenic mutations are plotted against their respective nucleotide positions within PKD1 coding sequence (cDNA designation, from 1 to 12 912, indicated on the lower part of the figure). The median nucleotide position for each group is represented by a star. PKD1 transcript is shown above.
Effect of clinical and genetic variables on the occurrence of IAs
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| Variables | n | HR | 95% CI | P-value | HR | 95% CI | P-value |
| Sex Male Female | 1185 1264 | 1.6 | 1.1–2.4 | 0.013 | 1.8 | 1.2–2.7 | 0.005 |
| Hypertension before 35 years No Yes | 1390 535 | 2.5 | 1.7–3.7 | <0.001 | 2.2 | 1.5–3.2 | <0.001 |
| Smoking status Never Past or active, <20 PY Past or active, >20 PY | 1275 799 207 | 1.1 1.6 | 0.7–1.7 0.9–2.7 | 0.575 0.095 | 1.3 2.1 | 0.9–2.1 1.2–3.7 | 0.176 0.009 |
| Genotype PKD1 PKD2 Unresolved | 1612 454 281 | 0.4 0.4 | 0.2–0.7 0.2–0.8 | 0.002 0.005 | 0.4 0.7 | 0.2–0.8 0.4–1.3 | 0.009 0.230 |
| PKD1 mutation type Non-truncating Truncating | 560 1052 | 1 | 0.6–1.5 | 0.957 | |||
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| Variables | n | HR | 95% CI | P-value | HR | 95% CI | P-value |
| Sex Male Female | 1185 1264 | 1.6 | 1.1–2.4 | 0.013 | 1.8 | 1.2–2.7 | 0.005 |
| Hypertension before 35 years No Yes | 1390 535 | 2.5 | 1.7–3.7 | <0.001 | 2.2 | 1.5–3.2 | <0.001 |
| Smoking status Never Past or active, <20 PY Past or active, >20 PY | 1275 799 207 | 1.1 1.6 | 0.7–1.7 0.9–2.7 | 0.575 0.095 | 1.3 2.1 | 0.9–2.1 1.2–3.7 | 0.176 0.009 |
| Genotype PKD1 PKD2 Unresolved | 1612 454 281 | 0.4 0.4 | 0.2–0.7 0.2–0.8 | 0.002 0.005 | 0.4 0.7 | 0.2–0.8 0.4–1.3 | 0.009 0.230 |
| PKD1 mutation type Non-truncating Truncating | 560 1052 | 1 | 0.6–1.5 | 0.957 | |||
Bold values indicate significant p-values (P<0.05).
Univariate and multivariable Cox regressions.
Abbreviation: n, number of subjects; HR, hazard ratio; CI, confidence interval.
Effect of clinical and genetic variables on the occurrence of IAs
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| Variables | n | HR | 95% CI | P-value | HR | 95% CI | P-value |
| Sex Male Female | 1185 1264 | 1.6 | 1.1–2.4 | 0.013 | 1.8 | 1.2–2.7 | 0.005 |
| Hypertension before 35 years No Yes | 1390 535 | 2.5 | 1.7–3.7 | <0.001 | 2.2 | 1.5–3.2 | <0.001 |
| Smoking status Never Past or active, <20 PY Past or active, >20 PY | 1275 799 207 | 1.1 1.6 | 0.7–1.7 0.9–2.7 | 0.575 0.095 | 1.3 2.1 | 0.9–2.1 1.2–3.7 | 0.176 0.009 |
| Genotype PKD1 PKD2 Unresolved | 1612 454 281 | 0.4 0.4 | 0.2–0.7 0.2–0.8 | 0.002 0.005 | 0.4 0.7 | 0.2–0.8 0.4–1.3 | 0.009 0.230 |
| PKD1 mutation type Non-truncating Truncating | 560 1052 | 1 | 0.6–1.5 | 0.957 | |||
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| Variables | n | HR | 95% CI | P-value | HR | 95% CI | P-value |
| Sex Male Female | 1185 1264 | 1.6 | 1.1–2.4 | 0.013 | 1.8 | 1.2–2.7 | 0.005 |
| Hypertension before 35 years No Yes | 1390 535 | 2.5 | 1.7–3.7 | <0.001 | 2.2 | 1.5–3.2 | <0.001 |
| Smoking status Never Past or active, <20 PY Past or active, >20 PY | 1275 799 207 | 1.1 1.6 | 0.7–1.7 0.9–2.7 | 0.575 0.095 | 1.3 2.1 | 0.9–2.1 1.2–3.7 | 0.176 0.009 |
| Genotype PKD1 PKD2 Unresolved | 1612 454 281 | 0.4 0.4 | 0.2–0.7 0.2–0.8 | 0.002 0.005 | 0.4 0.7 | 0.2–0.8 0.4–1.3 | 0.009 0.230 |
| PKD1 mutation type Non-truncating Truncating | 560 1052 | 1 | 0.6–1.5 | 0.957 | |||
Bold values indicate significant p-values (P<0.05).
Univariate and multivariable Cox regressions.
Abbreviation: n, number of subjects; HR, hazard ratio; CI, confidence interval.
Risk factors associated with diagnosis of IAs
To evaluate the association between the different clinical and genetic factors and the diagnosis of ruptured or unruptured IAs, univariate and multivariate Cox regression analyses were performed. In the univariate analysis, female sex, hypertension before age 35 years and PKD1 genotype were associated with an increased risk for the diagnosis of IA (Table 3). After the multivariate Cox regression that included 1737 subjects, these three variables remained independent predictors of the diagnosis of ruptured or unruptured IAs. In addition, smoking status, particularly when >20 PY, was also independently associated with the diagnosis of IAs (P = 0.009) (Table 3).
DISCUSSION
Widespread screening of IAs in ADPKD patients is currently not recommended, and pre-symptomatic screening was therefore conducted here only in patients with a positive family or a personal history of IAs or SAH, before major elective surgeries, or upon specific request after adequate information [30]. While these recommendations might change in the future, our study reflects current real-life clinical practice. We report here a prevalence of detected IAs in the Genkyst cohort, one of the largest population-based cohorts of ADPKD patients, of 4.65% (95% CI 3.56–5.74). As expected, this prevalence is therefore lower than that in systematic screening studies [9, 12]. Two recent studies, conducted at expert referral centres—Mayo Clinic, Rochester, MN, USA and Necker Hospital, Paris, France—and possibly reflecting more severely affected patients, report IA detection rates of ∼9.2% (n = 75) and ∼12.7% (n = 23) in 812 and 181 patients, respectively, who underwent pre-symptomatic screening (pre-symptomatic screening was performed in ∼27% and 35% of the Mayo and Necker cohorts) [29, 31].
We confirm here that a large majority of IAs in ADPKD patients are small and saccular, and located in the anterior circulation [9, 12, 29]. Approximately 26% of IA patients had multiple aneurysms. The median age at aneurysm rupture was 41.5 years, which is 10 years earlier than in the non-ADPKD population and consistent with previous studies [13, 15]. While IAs from the anterior circulation are considered at a lower risk of rupture in non-ADPKD patients, ∼87% of the ruptured IAs in our cohort originated from the anterior circulation.
Cumulative probabilities of diagnosis of IA in this population-based cohort provide new and interesting information, which should, however, be interpreted with caution, as individuals with ruptured IAs, particularly at younger ages, might be underrepresented. At 70 years of age, the cumulative probabilities for the diagnosis of IA or past history of ruptured IAs were 8.1% and 3.2%, respectively. Strikingly, cumulative probabilities of diagnosis of IA and ruptured IAs appear to be higher in women, especially after 50 years, which was not reported in ADPKD patients until now. This parallels observations made in the non-ADPKD population and suggests a possible protective role of oestrogens [11]. Several former studies support a role for oestrogen deficiency, causing a reduction in the collagen content of tissues, which might contribute to aneurysm development in postmenopausal women, similar to patients with connective tissue disorders. In the non-ADPKD population, an earlier age at menopause is associated with a higher risk for IAs, and animal and clinical studies have suggested a protective role of hormone replacement therapy (HRT) against SAH [37–39]. Whether HRT should be recommended for women with ADPKD at increased risk for IAs, i.e. with a positive familial history for IAs, will require further studies.
Importantly, our study allows revisiting the influence of genetics on IA development in ADPKD in light of modern genomics tools in a large cohort of patients. The diagnosis rate of ruptured and unruptured IAs was >2-fold higher in carriers of mutations in PKD1 than in PKD2, with respective cumulative probabilities of 8.1% versus 2.8% at age 60 years. The PKD1 genotype remained significantly associated with diagnosis of IAs after the multivariate analysis. Confounding factors may partially account for this observation: first, early IA rupture, before the diagnosis of ADPKD, might occur in some PKD2 mutation carriers; and second, pre-symptomatic screening might be more frequently conducted in PKD1 mutation carriers, who generally have more significant FHs and more severe renal disease, resulting in an earlier ADPKD diagnosis and closer medical follow-up [35]. However, the consistent observation of a higher rate of diagnosis of ruptured IAs in PKD1 mutation carriers and the results of the multivariate Cox analyses, showing that this association is independent of age at hypertension diagnosis, suggest that PKD1 mutation carriers might be more at risk of developing IAs. Severe vascular phenotypes have been described in both Pkd1 and Pkd2 murine models [20–23, 40]. The reasons for this apparent higher risk for IAs in PKD1 patients remain to be understood. In contrast to a study from the early 2000s, we did not identify any correlation between the occurrence of IAs and the localization of mutations along the PKD1 gene [25]. While truncating pathogenic variants of PKD1 are known to be associated with poorer renal prognosis, no association between PKD1 mutation type and diagnosis of IAs was identified [33]. We did not identify any recurring PKD1 or PKD2 mutations among individuals with IAs. Former studies reported IAs in unrelated families harbouring a two base-pair deletion in PKD1 (c.5014_5015delAG), suggesting an association with this specific mutation, but more systematic genetic testing in ADPKD patients has now established that this variant is in fact the most common pathogenic variant of PKD1 (∼1–2%) [25, 41]. In the small subgroup of 39 patients harbouring mutations in other genes, no diagnosis of IA was reported. However, IAs were occasionally reported in GANAB pedigrees, and various vascular phenotypes, including IAs, dilatation of the thoracic aorta and dissection of a carotid artery, were recently described in a cohort of DNAJB11 mutation carriers [42].
Studies in the non-ADPKD population have identified risk factors associated with IAs. These include non-modifiable factors such as female sex, ethnicity, and personal or FH of ruptured or unruptured aneurysm, and modifiable factors such as smoking exposure and hypertension [11, 27, 43–45]. In a recent study conducted in the Mayo Clinic cohort, hypertension and smoking history were significantly more frequent in ADPKD patients with IAs [29]. In our study, after multivariate Cox analysis, four factors remained independently associated with the diagnosis of IA: female sex, hypertension before age 35 years, smoking status and PKD1 genotype.
Because IA diagnosis was made by targeted screening in the context of a positive familial history in a majority of the IA subjects, this risk factor could not be entered into the multivariate analysis. However, the importance of a positive FH should be stressed. The observation of pedigrees with a strong familial clustering of IAs in our cohort and others suggests the role of genetic modifiers hitherto unidentified. Using genome-wide association studies, whole-exome sequencing and/or RNA sequencing, some candidate genes involved in the development of IAs have already been identified in the general population [44, 46]. Similar strategies might be successful in identifying such modifiers in ADPKD but will require the enrolment of large numbers of participants and international collaborative efforts.
This study has some limitations. Data on the number of ADPKD-affected individuals who underwent screening for IAs and in whom no IA was detected are lacking, and this information could not be collected retrospectively. Because targeted screening was employed, the number of IAs may have been underestimated. However, the data presented here reflect real-life practice and are hence likely to be of interest in clinical practice.
In conclusion, the determinants of the development of IAs in ADPKD patients are complex and multifactorial. Female sex, PKD1 genotype, early-onset hypertension, smoking exposure and positive familial history for IAs are associated with a higher risk for diagnosis of IA.
ACKNOWLEDGEMENTS
We thank the patients and families for involvement in the study. We would also like to acknowledge the study coordinators Christelle Guillerm-Regost, Christelle Ratajczak and Noée Gales (CHU Brest, France), Fabien Duthé (CHU Poitiers, France), Bernadette Pilorge et Julien Bontemps (CHU Tours), Sylvie Le Stum and David Naveiro (CHU Rennes), Béatrice Mazé and Eléonore Ourouda (CHU Angers), Véronique Bihel et Stéphane Natur (CH Saint Malo), Alexandra Bréant (CH Lorient), Bénédicte Hue (CH Saint Brieuc), Pauline Le Floch (CH Saint Nazaire), Angélique Colin (ECHO), Edwige Migne et Hélène Pelerin (CH La Roche sur Yon) and Fanny Biais-Sauvêtre (CH La Rochelle).
FUNDING
The study was supported by a National Plan for Clinical Research (PHRC inter-regional GeneQuest, NCT02112136, ECLG), a grant by the French Association for Information and Research on Genetic Kidney Diseases (AIRG France, ECLG), a grant from Otsuka Pharmaceuticals Industry (YLM) and a National Research Agency grant (ANR JCJC 2019 GENOVAS-PKD, R19145NN, ECLG).
CONFLICT OF INTEREST STATEMENT
None declared. The results presented in this paper have not been published previously in whole or part, except in abstract format (ERA-EDTA 2019).
Appendix
Genkyst/GeneQuest Investigators
We would like to thank Genkyst/GeneQuest investigators: Drs A. Grall-Jezequel, M.C. Moal, C. Hanrotel-Saliou, I. Segalen, T. Tanquerel, L. Lanfranco, V.T. Huynh, A. Capdeville (Centre Hospitalier Régional Universitaire, Brest); M.P. Morin, P. Le Pogamp, S. Gie, J. Rivalan, E. Laruelle, C. Richer, N. Lorcy, L. Golbin, M. Terrasse, S. Morice, H. Brenier, A. Michel, A. Lavergne, E. Tomkiewicz (Centre Hospitalier Universitaire, Rennes); P. Gatault, E. Merieau, C. Barbet, M. Buchler, G. Golea, L. Ghouti, D. Gautard, B. Sautenet, M. François, A. Fournier, C. Baron, C. Salmon, N. Rabot, L. Prat, J.F. Valentin, B. Birmele, C. Geneste, A. Goumard, E. Chevallier, F. Von Ey (Centre Hospitalier Régional Universitaire, Tours); E. Desport, A. Thierry, G. Touchard, M. Belmouaz, V. Javaugue, M.A. Bauwens, F. Fride-Leroy, I. Bouteau, A. Sibille, P. Jamet, F. Joly, L. Dufour (Centre Hospitalier Universitaire, Poitiers); J.F. Subra, V. Besson, M. Cousin, J. Sayegh, C. Onno, M.N. Maghakian, J. Demiselle, A.S. Garnier, M. Planchais, F. Guibert, C. Deschamps (Centre Hospitalier Universitaire, Angers); C. Stanescu, P. Le Cacheux, S. Baluta, F. Leonetti (†), R. Boulahrouz, M.L. Ferrier, C. Freguin, A. Simon, J. Potier, J.M. Coulibaly, A. Colombo, A. Delezire (Centre Hospitalier Yves le Foll, Saint Brieuc); T. Dolley-Hitze (Centre Hospitalier Broussais, Saint Malo); E. Michez, L. Mandart, V. Menoyo, E. Pincon, C. Muresan, P.Y. Durand, I. Wegner (Centre Hospitalier de Bretagne Atlantique, Vannes); I. Metes, T. Guyon-Roger, B. Wehbe, P. Siohan, C. Drouet, C. Lohéac (Centre Hospitalier de Cornouaille, Quimper); A. Le Guillou, M. Le Jeune, G. Belliard, L. Corlu, T. Sawadogo, S. Georgescu (Centre Hospitalier de Bretagne Sud, Lorient); P. Jousset, R. Latif, M. Massad (Centre Hospitalier du Centre Bretagne, Pontivy); J.P. Jaulin, G. Couvrat-Desvergnes, A.H. Querard, J.N. Ottavioli, N. Target, A. Chapal, A. Le Fur (Centre Hospitalier Départemental de Vendée, La Roche sur Yon); D. Besnier, S. Regnier-Le Coz, A. Blanpain, S. Durault, D. Larmet, A. Skandri (Centre Hospitalier Georges Charpak, Saint-Nazaire); L.M. Pouteau (Centre Hospitalier de Laval); D. Labatut (Centre Hospitalier de Niort); C. Bachelet-Rousseau, S. Delbes, F. Pourreau (Centre Hospitalier de La Rochelle); J.P. Coindre, M. Sigogne, G.B. Piccoli, H. Nzeyimana (Centre Hospitalier Le Mans); S. Mzoughi (Centre Perharidy, Roscoff); M.P. Guillodo, P. Depraetre, B. Strullu, E. Chaffara, M. Le Mee, M. Gosselin (Association des Urémiques de Bretagne, Brest-Morlaix); N. Terki, K. Goulesque (Centre de Néphrologie et de Dialyse d'Armorique, Brest); S. Benarbia, M. Dimulescu, M. Rifaat (Association des Urémiques de Bretagne, Quimper); D. Legrand, G. Duneau, E. Georges (Association des Urémiques de Bretagne, Lorient); F. Babinet, S. Lanoiselee (ECHO, Le Mans); C. Savoiu, A. Testa, I. Oancea, I. Coupel, S. Parahy, G. Lefrancois, D. Hristea, M. Joly (ECHO, Nantes); E. Briand, D. Bugnon, S. Martin (ECHO les Sables d'Olonne).
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