Relationship of Seminal Megavesicles, Prostate Median Cysts, and Genotype in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) can involve prostate and seminal vesicles but the potential interrelationship of these findings and associations with PKD gene mutation locus and type is unknown. PURPOSE: To determine the interrelationship of seminal megavesicles (seminal vesicles with lumen diameter > 10mm) and prostatic cysts in ADPKD and to determine whether there are associations with PKD gene mutations. STUDY TYPE: Retrospective, case control. POPULATION: Male ADPKD subjects (n = 92) with mutations in PKD1 (n = 71; 77%) or PKD2 (n = 21; 23%), and age/gender-matched controls without ADPKD (n = 92). FIELD STRENGTH/SEQUENCE: 1.5T, axial/coronal T2 -weighted MR images. ASSESSMENT: Reviewers blinded to genotype independently measured seminal vesicle lumen diameter and prevalence of cysts in prostate, kidney, and liver. STATISTICAL TESTS: Nonparametric tests for group comparisons and univariate and multivariable logistic regression analyses to identify associations of megavesicles and prostate median cysts with mutations and renal/hepatic cyst burden. RESULTS: Seminal megavesicles were found in 23 of 92 ADPKD (25%) subjects with PKD1 (22/71, 31%) or PKD2 (n = 1/21, 5%) mutations, but in only two control subjects (P < 0.0001). Prostate median cysts were found in 17/92 (18%) ADPKD subjects, compared with only 6/92 (7%) controls (P = 0.01), and were correlated with seminal vesicle diameters (ρ = 0.24, P = 0.02). Nonmedian prostate cyst prevalence was identical between ADPKD and controls (7/92, 8%). After adjusting for age, estimated glomerular filtration rate, and height-adjusted total kidney volume, ADPKD subjects with megavesicles were 10 times more likely to have a PKD1 than a PKD2 mutation. Among PKD1 subjects, seminal megavesicles occurred more frequently with nontruncating mutations with less severe kidney involvement. DATA CONCLUSION: ADPKD is associated with prostate median cysts near ejaculatory ducts. These cysts correlate with seminal megavesicles (dilated to >10 mm) which predict a 10-fold greater likelihood of PKD1 vs. PKD2 mutation. Cysts elsewhere in the prostate are not related to ADPKD. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:894-903.

Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in PKD1 and PKD2 that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism. METHODS: We characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in PKD1 and PKD2 genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in PKD1 or PKD2 was identified. RESULTS: Complete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of PKD1 or PKD2 were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No trans-heterozygous mutations of PKD1 or PKD2 genes were identified. Copy number changes of PKD1 ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non-PKD1/2 genes, including other ciliopathy genes and cancer-related genes. CONCLUSIONS: These findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of PKD1 or PKD2 in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.

Pancreatic Cysts in Autosomal Dominant Polycystic Kidney Disease: Prevalence and Association with PKD2 Gene Mutations.

Purpose To define the magnetic resonance (MR) imaging prevalence of pancreatic cysts in a cohort of patients with autosomal dominant polycystic kidney disease (ADPKD) compared with a control group without ADPKD that was matched for age, sex, and renal function. Materials and Methods In this HIPAA-compliant, institutional review board-approved study, all patients with ADPKD provided informed consent; for control subjects, informed consent was waived. Patients with ADPKD (n = 110) with mutations identified in PKD1 or PKD2 and control subjects without ADPKD or known pancreatic disease (n = 110) who were matched for age, sex, estimated glomerular filtration rate, and date of MR imaging examination were evaluated for pancreatic cysts by using axial and coronal single-shot fast spin-echo T2-weighted images obtained at 1.5 T. Total kidney volume and liver volume were measured. Univariate and multivariable logistic regression analyses were conducted to evaluate potential associations between collected variables and presence of pancreatic cysts among patients with ADPKD. The number, size, location, and imaging characteristics of the cysts were recorded. Results Patients with ADPKD were significantly more likely than control subjects to have at least one pancreatic cyst (40 of 110 patients [36%] vs 25 of 110 control subjects [23%]; P = .027). In a univariate analysis, pancreatic cysts were more prevalent in patients with ADPKD with mutations in PKD2 than in PKD1 (21 of 34 patients [62%] vs 19 of 76 patients [25%]; P = .0002). In a multivariable logistic regression model, PKD2 mutation locus was significantly associated with the presence of pancreatic cysts (P = .0004) and with liver volume (P = .038). Patients with ADPKD and a pancreatic cyst were 5.9 times more likely to have a PKD2 mutation than a PKD1 mutation after adjusting for age, race, sex, estimated glomerular filtration rate, liver volume, and total kidney volume. Conclusion Pancreatic cysts were more prevalent in patients with ADPKD with PKD2 mutation than in control subjects or patients with PKD1 mutation. (©) RSNA, 2016 Online supplemental material is available for this article.

Cisterna chyli in autosomal dominant polycystic kidney disease.

PURPOSE: After observing prominent cisterna chyli in several patients with autosomal dominant polycystic kidney disease (ADPKD), we investigated the potential association of cistern chyli enlargement with ADPKD. MATERIALS AND METHODS: Retrospective, cross-sectional analysis of abdominal and pelvic MRI at 1.5 Tesla (T) in 70 ADPKD patients (male 44.3%, 20-83 years, median = 53 years) were compared with 70 age and gender matched control subjects without ADPKD, cirrhosis, or cholestasis. Cisterna chyli diameter was measured on axial single shot fast spin echo (SSFSE) images at the level of T12-L2 and evaluated by multivariable regression models with covariates including estimated glomerular filtration rate (eGFR), total kidney volume (TKV), renal cyst fraction (cyst volume/kidney volume), and liver volume. RESULTS: Subjects with ADPKD had larger median cisterna chyli diameter compared with those without ADPKD (6.1 mm versus 3.4 mm, P < 0.0001). The prevalence of cisterna chyli enlargement more than the median (3.4 mm), was greater in ADPKD than in controls (99% versus 51%, P < 0.0001). On univariate analysis, cisterna chyli diameter was inversely correlated with eGFR (r = -0.41; P < 0.0001) and directly correlated with TKV (r = 0.57; P < 0.0001), total renal cyst fraction (r = 0.61; P < 0.001), and liver volume (r = 0.17; P = 0.040). Multivariable linear regression modeling found a significant association of cisterna chyli diameter with ADPKD diagnosis (B = 2.14; 95% confidence interval [CI]: 0.05-4.23; P = 0.04). Logistic regression analysis confirmed the association of ADPKD with an enlarged cisterna chyli diameter (odds ratio = 68.4; 95%CI: 8.9-524, P < 0.0001). CONCLUSION: Enlarged cisterna chyli is highly prevalent in ADPKD patients but not in age and gender-matched controls.

Papillary renal cell carcinoma with a somatic mutation in MET in a patient with autosomal dominant polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 and is characterized by proliferation of renal tubular epithelium and progressive chronic kidney disease. Derangements in similar cellular signaling pathways occur in ADPKD and renal malignancies, although an association of these disorders has not been established. Herein, we present a case of papillary RCC (pRCC) incidentally discovered in a patient with ADPKD following bilateral native nephrectomy during renal transplantation. Whole exome sequencing of the pRCC found a somatic missense mutation in MET proto-oncogene, p.Val1110Ile, not present in kidney cyst epithelium or non-cystic tissue. RNA sequencing demonstrated increased mRNA expression of MET and pathway-related genes, but no significant copy number variation of MET was detected. Genetic analysis of PKD genes from peripheral blood lymphocytes and renal cyst epithelium identified a constitutional PKD1 germline mutation, p.Trp1582Ser, predicted to be pathogenic. Unique somatic mutations in PKD1 were also detected in 80% of the renal cysts analyzed, but not in the pRCC. These results suggest that, in this patient, the pRCC utilized a signaling pathway involving MET that was distinct from the pathogenesis of ADPKD. This is the first report of PKD1 mutations and a somatic mutation of the MET oncogene in a pRCC in ADPKD.