• Tolvaptan
• autosomal dominant polycystic kidney disease (ADPKD)
• end-stage kidney disease (ESKD)
• hemodialysis
• mortality

• Humans
• Tolvaptan/therapeutic use
• Polycystic Kidney, Autosomal Dominant/complications
• Polycystic Kidney, Autosomal Dominant/drug therapy
• Male
• Female
• Middle Aged
• Retrospective Studies
• Glomerular Filtration Rate
• Adult
• Kidney Failure, Chronic/therapy
• Kidney Failure, Chronic/etiology
• Antidiuretic Hormone Receptor Antagonists/therapeutic use
• Propensity Score
• Renal Dialysis
• Treatment Outcome

• ADPKD
• biomarkers
• polycystic kidney disease
• predictive model
• prognosis
• total kidney volume

• Humans
• Kidney Transplantation
• Nephrectomy
• Retrospective Studies
• Male
• Female
• Polycystic Kidney Diseases/surgery
• Polycystic Kidney Diseases/complications
• Adult
• Middle Aged
• Graft Survival
• Treatment Outcome
• Kidney Failure, Chronic/surgery

• Humans
• Polycystic Kidney, Autosomal Dominant/metabolism
• Polycystic Kidney, Autosomal Dominant/diagnosis
• Polycystic Kidney, Autosomal Dominant/complications
• Disease Progression
• Biomarkers/metabolism
• Intra-Abdominal Fat/metabolism
• Obesity, Abdominal/metabolism
• Obesity, Abdominal/complications
• Adiposity

Among patients with severe polycystic liver disease (PLD) (height-adjusted total liver volume of <1800 ml/m), PKD2 variants were found in 34%. Three patients with PKD1 or PKD2 variants are reported with severe PLD but normal-sized kidneys (hTKV of < 250 ml/m).

Polycystic liver disease (PLD) is present in most patients with autosomal dominant polycystic kidney disease (ADPKD). PLD can alternatively be found with few, if any, kidney cysts as a diagnosis of isolated PLD (autosomal dominant PLD [ADPLD]). Several genes are identified as causative for this spectrum of phenotypes; however, the relative incidence of genetic etiologies among patients with severe PLD is unknown.

Patients with ADPKD or ADPLD having severe PLD defined as height-adjusted total liver volume (hTLV) >1800 ml/m were recruited. Subsequent clinical care was followed. Genetic analysis was performed using whole exome sequencing.

We enrolled and sequenced 49 patients (38 women, 11 men). Pathogenic or suspected pathogenic variants in polycystic disease genes were found in 44 of 49 patients (90%). The disease gene was PKD1 in 20 of 44 patients (45%), PKD2 in 15 of 44 patients (34%), PRKCSH in 5 of 44 patients (11%), GANAB in 2 of 44 patients (5%), SEC63 in 1 of 44 patients (2%), and ALG8 in 1 of 44 patients (2%). The median hTLV was no different between genetically defined ADPKD and ADPLD groups (4431 [range, 1817–9148] versus 3437 [range, 1860–8211]) ml, P = 0.77), whereas height-adjusted kidney volume was larger as expected in ADPKD than in ADPLD (607 [range, 190–2842] versus 179 [range, 138–234] ml/m, P < 0.01). Of the clinically defined ADPKD patients, 20 of 38 patients (53%) were PKD1 , 15 of 38 (39%) were PKD2 , and 3 (8%) remained genetically unsolved. Among patients with a pathogenic PKD1 or PKD2 variant, we found three patients with a liver-dominant ADPKD (severe PLD with height-adjusted total kidney volume <250 ml/m).

ADPLD-related genes represent 20% of patients with severe PLD in our cohort. Of those enrolled with ADPKD, we observed a higher frequency of PKD2 carriers than in any previously reported ADPKD cohorts. Although there was no significant difference in the hTLV between patients with PKD1 and PKD2 in this cohort, our data suggest that enrollment on the basis of severe PLD may enrich for patients with PKD2 .

• adpkd
• cystic kidney
• gene expression
• polycystic kidney disease

• Humans
• Japan
• Liver Diseases/genetics
• Cysts/genetics
• Cysts/pathology
• Female
• Male
• Genetic Testing
• Adult
• Mutation

• K08 DK119642 NIDDK NIH HHS
• Okinaka Memorial Institute for Medical Research

• Humans
• Polycystic Kidney, Autosomal Dominant/genetics
• Polycystic Kidney, Autosomal Dominant/diagnosis
• TRPP Cation Channels/genetics
• High-Throughput Nucleotide Sequencing
• Multiplex Polymerase Chain Reaction/methods
• Female

• ADPKD
• PKD1
• kidney length
• progression
• total kidney volume

• Humans
• Polycystic Kidney, Autosomal Dominant/genetics
• Polycystic Kidney, Autosomal Dominant/pathology
• Male
• Disease Progression
• Female
• Genotype
• Cross-Sectional Studies
• Adult
• Middle Aged
• Kidney/pathology
• Kidney/diagnostic imaging
• Prognosis
• Glomerular Filtration Rate
• Follow-Up Studies
• TRPP Cation Channels/genetics
• Body Height/genetics

• MR/R01745X/1 Medical Research Council
• Academy of Medical Sciences

• ADPKD
• Schwartz
• children
• hyperfiltration
• quadratic formula

• Autosomal dominant polycystic kidney disease
• Genetic decisions
• Medically assisted reproduction
• Novel variants
• PKD1
• PKD2

• Humans
• Female
• TRPP Cation Channels/genetics
• Adult
• Polycystic Kidney, Autosomal Dominant/genetics
• Mutation, Missense
• Genetic Testing
• Pedigree
• Preimplantation Diagnosis

• ADPKD
• Hemodialysis
• Kidney transplantation
• Living donor
• Nephrectomy
• Peritoneal dialysis

• Humans
• Renal Dialysis
• Polycystic Kidney, Autosomal Dominant/complications
• Peritoneal Dialysis/adverse effects
• Kidney Transplantation/adverse effects

• ADPKD
• aquaretic adverse effects
• prediction for ESKD
• tolvaptan

• ABPM
• Autosomal dominant polycystic kidney disease
• Nephromegaly
• PKD1

• Male
• Humans
• Child
• Female
• Polycystic Kidney, Autosomal Dominant/complications
• Polycystic Kidney, Autosomal Dominant/genetics
• Retrospective Studies
• Hypertension/epidemiology
• Hypertension/genetics
• Hypertension/diagnosis
• Phenotype
• Parents

• ADPKD
• ARPKD
• PKD
• cystic kidney disease
• polycystic kidney disease

• Adult
• Pregnancy
• Female
• Child
• Humans
• Polycystic Kidney, Autosomal Recessive/diagnosis
• Polycystic Kidney, Autosomal Recessive/genetics
• Polycystic Kidney, Autosomal Recessive/therapy
• Kidney
• Polycystic Kidney, Autosomal Dominant/complications
• Polycystic Kidney, Autosomal Dominant/diagnosis
• Polycystic Kidney, Autosomal Dominant/genetics
• Kidney Neoplasms
• Cysts/diagnosis
• Cysts/genetics
• Cysts/therapy

• ADPKD
• PKD1 mutation
• analysis of germline mutations
• biomarkers
• predicting renal prognosis

• OAK-ISS-2018-000479 Otsuka (Japan)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian kidney disease, affecting approximately one in 1,000 births and accounting for 5% of end-stage kidney disease in developed countries. The pathophysiology of ADPKD is strongly linked to metabolic dysregulation, which may be secondary to defective polycystin function. Overweight and obesity are highly prevalent in patients with ADPKD and constitute an independent risk factor for progression. Recent studies have highlighted reduced AMP-activated protein kinase (AMPK) activity, increased mammalian target of rapamycin (mTOR) signaling, and mitochondrial dysfunction as shared pathobiology between ADPKD and overweight/obesity. Notably, mTOR and AMPK are two diametrically opposed sensors of energy metabolism that regulate cell growth and proliferation. However, treatment with the current generation of mTOR inhibitors is poorly tolerated due to their toxicity, making clinical translation difficult. By contrast, multiple preclinical and clinical studies have shown that pharmacological activation of AMPK provides a promising approach to treat ADPKD. In this narrative review, we summarize the pleiotropic functions of AMPK as a regulator of cellular proliferation, macromolecule metabolism, and mitochondrial biogenesis, and discuss the potential for pharmacological activation of AMPK to treat ADPKD and obesity-related kidney disease.

• Functional effect
• Mutation
• PKD1 gene
• PKD2 gene
• Single nucleotide polymorphism

• Autosomal dominant polycystic kidney disease
• Cardiac dysfunction
• Lipid derangement
• Metabolic rewiring
• Mitochondria
• Polycystin-1 cleavage at GPS

• Animals
• Heart
• Mice
• Mitochondria/metabolism
• Mutation
• Polycystic Kidney, Autosomal Dominant/genetics
• Polycystic Kidney, Autosomal Dominant/metabolism
• TRPP Cation Channels/genetics
• TRPP Cation Channels/metabolism

• P30 DK090868 NIDDK NIH HHS
• U54 DK126114 NIDDK NIH HHS
• R01 DK111611 NIDDK NIH HHS

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and shows a wide phenotype. Only patients with rapid progression (RP) are included in clinical trials or are approved to receive disease-modifying drugs. This study aims at comparing different available predictive tools in ADPKD with the Mayo classification (MC) identification of rapid progressors based on high total kidney volume (TKV) according to age.

A total of 164 ADPKD patients were recruited retrospectively from a single centre. The performance of diverse tools to identify RP defined as being in MC categories 1C–1E was assessed.

A total of 118 patients were MC 1C–1E. The algorithm developed by the European Renal Association–European Dialysis and Transplant Association Working Group on Inherited Kidney Disorders/European Renal Best Practice had a low sensitivity in identifying MC 1C–1E. The sensitivity and specificity of TKV to predict RP depend on the cut-off used. A kidney length of >16.5 cm before age 45 years has high specificity but low sensitivity. Assessing the MC by ultrasonography had high levels of agreement with magnetic resonance imaging (MRI) data, especially for 1A, 1D and 1E. The estimated glomerular filtration rate (eGFR) decline was very sensitive but had low specificity. In contrast, the Predicting Renal Outcome in Polycystic Kidney Disease (PROPKD) score was very specific but had poor sensitivity. Having hypertension before 35 years of age is a good clinical predictor of MC 1C–1E. Family history can be of help in suggesting RP, but by itself it lacks sufficient sensitivity and specificity.

The MC by ultrasonography could be an option in hospitals with limited access to MRI as it performs well generally, and especially at the extremes of the MC, i.e. classes 1A, 1D and 1E. The eGFR decline is sensitive but not very specific when compared with the MC, whereas the PROPKD score is very specific but has low sensitivity. Integrating the different tools currently available to determine RP should facilitate the identification of rapid progressors among patients with ADPKD.

Valid prediction models or predictors of disease progression in children and young patients with autosomal dominant polycystic kidney disease (ADPKD) are lacking. Although total kidney volume (TKV) and Mayo imaging classification are generally used to predict disease progression in patients with ADPKD, it remains unclear whether germline mutation types are associated with these factors. We therefore investigated the association between mutation type and TKV and Mayo imaging classification among patients with ADPKD.

A total of 129 patients with ADPKD who underwent genetic analyses were enrolled in the study. The associations between the severity of PKD (TKV ≥ 1000 ml and Mayo classes 1C–1E) and the PKD1 mutation types (nonsense mutation, frameshift or splicing mutation, and substitution) were evaluated.

Among the mutation types, only PKD1 splicing/frameshift mutation had significant associations with TKV ≥ 1000 ml in sex-adjusted and multivariable logistic analyses. Similarly, only the PKD1 splicing/frameshift mutation was significantly associated with Mayo 1C–1E in sex-adjusted and multivariable logistic analyses. PKD1 nonsense mutation, PKD1 substitution, or PKD1 mutation position had no significant association with TKV ≥ 1000 ml or Mayo 1C–1E.

Kidney cyst severity differs according to the mutation types in PKD1. Patients with PKD1 splicing mutations or PKD1 frameshift mutations are associated with TKV ≥ 1000 ml or Mayo 1C–1E. Detailed assessment of mutation types may be useful for predicting renal prognosis in patients with ADPKD and may especially contribute to the care of a high-risk group of children with ADPKD.

• genetics
• molecular biology
• cardiology
• diseases
• nephrology

• Animals
• Mice
• TRPP Cation Channels/genetics
• TRPP Cation Channels/deficiency
• TRPP Cation Channels/metabolism
• Phenotype
• Kidney/pathology
• Kidney/metabolism
• Apoptosis
• Smoking/adverse effects
• Fibrosis
• Cell Proliferation
• Polycystic Kidney, Autosomal Dominant/pathology
• Polycystic Kidney, Autosomal Dominant/metabolism
• Polycystic Kidney, Autosomal Dominant/genetics
• Female
• Disease Models, Animal
• Mice, Knockout
• Male
• Kidney Diseases, Cystic/pathology
• Kidney Diseases, Cystic/metabolism
• Kidney Diseases, Cystic/genetics
• Kidney Diseases, Cystic/etiology
• Glutathione/metabolism
• Disease Progression

• P30 DK090868 NIDDK NIH HHS
• No funding

• Ehlers‐Danlos syndrome
• Loeys‐Dietz syndrome
• MASS phenotype
• Marfan
• heart failure
• mitral regurgitation
• mitral valve prolapse

• Disease Progression
• Ehlers-Danlos Syndrome/diagnosis
• Ehlers-Danlos Syndrome/epidemiology
• Ehlers-Danlos Syndrome/physiopathology
• Hemodynamics
• Humans
• Loeys-Dietz Syndrome/diagnosis
• Loeys-Dietz Syndrome/epidemiology
• Loeys-Dietz Syndrome/physiopathology
• Marfan Syndrome/diagnosis
• Marfan Syndrome/epidemiology
• Marfan Syndrome/physiopathology
• Mitral Valve Insufficiency/diagnosis
• Mitral Valve Insufficiency/epidemiology
• Mitral Valve Insufficiency/physiopathology
• Mitral Valve Insufficiency/surgery
• Mitral Valve Prolapse/diagnosis
• Mitral Valve Prolapse/epidemiology
• Mitral Valve Prolapse/physiopathology
• Mitral Valve Prolapse/surgery
• Myopia/diagnosis
• Myopia/epidemiology
• Myopia/physiopathology
• Prevalence
• Risk Factors
• Skin Diseases/diagnosis
• Skin Diseases/epidemiology
• Skin Diseases/physiopathology
• Treatment Outcome

• R01 HL149696 NHLBI NIH HHS
• R01 HL131546 NHLBI NIH HHS
• R25 GM113278 NIGMS NIH HHS
• C06 RR018823 NCRR NIH HHS
• T32 HL007260 NHLBI NIH HHS
• P20 GM103444 NIGMS NIH HHS
• National Institutes of Health
• American Heart Association

• ADPKD
• genetic kidney disease
• human genetics
• mutation
• polycystic kidney disease

• Adult
• Female
• Humans
• Male
• Middle Aged
• Mutation
• Polycystic Kidney, Autosomal Dominant/genetics
• Severity of Illness Index
• TRPP Cation Channels/genetics

• CIHR

• Autosomal-dominant polycystic kidney disease (ADPKD)
• disease progression
• height-adjusted TKV (htTKV)
• imaging classification
• kidney cyst growth
• kidney failure
• prognostic biomarker
• rapid progressor
• renal function trajectory
• renoprotective drug
• review
• tolvaptan
• total kidney volume (TKV)
• vasopressin V(2) receptor antagonist

• ADPKD
• NGS
• PKD1
• PKD2
• cystogenes
• polycystic kidney disease

• genetic testing
• next-generation sequencing
• polycystic kidney disease

• PKD1
• PKD2
• mutation
• polycystic kidney disease
• renal prognosis
• renal progression

Total kidney volume (TKV) is a validated prognostic biomarker for risk assessment in autosomal dominant polycystic kidney disease (ADPKD). TKV by manual segmentation (MS) is the “gold standard” but is time-consuming and requires expertise. The purpose of this study was to compare TKV-based prognostic performance by ellipsoid (EL) vs. MS in a large cohort of patients. Cross-sectional study of 308 patients seen at a tertiary referral center; all had a standardized MRI with typical imaging of ADPKD. An experienced radiologist blinded to patient clinical results performed all TKV measurements by EL and MS. We assessed the agreement of TKV measurements by intraclass correlation(ICC) and Bland-Altman plot and also how the disagreement of the two methods impact the prognostic performance of the Mayo Clinic Imaging Classification (MCIC). We found a high ICC of TKV measurements (0.991, p < 0.001) between EL vs. MS; however, 5.5% of the cases displayed disagreement of TKV measurements >20%. We also found a high degree of agreement of the individual MCIC risk classes (i.e. 1A to 1E) with a Cohen’s weighted-kappa of 0.89; but 42 cases (13.6%) were misclassified by EL with no misclassification spanning more than one risk class. The sensitivity and specificity of EL in distinguishing low-risk (1A-B) from high-risk (1C-E) MCIC prognostic grouping were 96.6% and 96.1%, respectively. Overall, we found an excellent agreement of TKV-based risk assessment between EL and MS. However, caution is warranted for patients with MCIC 1B and 1C, as misclassification can have therapeutic consequence.

• ADPKD
• genetics
• polycystic kidney disease

• ADPKD (autosomal dominant polycystic kidney disease)
• Canadian consensus
• disease progression
• kidney
• risk

• Otsuka Pharmaceutical

• Autosomal dominant polycystic kidney disease (ADPKD)
• PKD1
• PKD2
• assisted reproductive technology
• end-stage renal disease (ESRD)
• genetic counseling
• in vitro fertilization (IVF)
• linkage analysis
• mutation detection
• pregnancy
• preimplantation genetic diagnosis (PGD)

• Biomarker
• Copeptin
• Polycystic kidney disease

• ADPKD
• ARPKD
• Polycystic kidney disease
• Tolvaptan
• Vasopressin
• cAMP

• PROPKD score
• autosomal dominant polycystic kidney disease
• patient selection
• rapid progression
• tolvaptan
• total kidney volume

• MR/M012212/1 Medical Research Council

• biomedical research
• chronic kidney disease
• clinical trials
• knowledge translation
• nephrology
• patient engagement
• patient-oriented research

• Canadian Institutes of Health Research

ADPKD is erroneously perceived as a not rare condition, which is mainly due to the repeated citation of a mistaken interpretation of old epidemiological data, as reported in the Dalgaard's work (1957). Even if ADPKD is not a common condition, the correct prevalence of ADPKD in the general population is uncertain, with a wide range of estimations reported by different authors. In this work, we have performed a meta-analysis of available epidemiological data in the European literature. Furthermore we collected the diagnosis and clinical data of ADPKD in a province in the north of Italy (Modena). We describe the point and predicted prevalence of ADPKD, as well as the main clinical characteristics of ADPKD in this region.

We looked at the epidemiological data according to specific parameters and criteria in the Pubmed, CINAHL, Scopus and Web of Science databases. Data were summarized using linear regression analysis. We collected patients’ diagnoses in the Province of Modena according to accepted clinical criteria and/or molecular analysis. Predicted prevalence has been calculated through a logistic regression prediction applied to the at-risk population.

The average prevalence of ADPKD, as obtained from 8 epidemiological studies of sufficient quality, is 2.7: 10,000 (CI95 = 0.73–4.67). The point prevalence of ADPKD in the province of Modena is 3.63: 10,000 (CI95 = 3.010–3.758). On the basis of the collected pedigrees and identification of the at-risk subjects, the predicted prevalence in the Province of Modena is 4.76: 10,000 (CI 95% = 4.109–4.918).

As identified in our study, point prevalence is comparable with the majority of the studies of literature, while predicted prevalence (4.76: 10,000) generally appears higher than in the previous estimates of the literature, with a few exceptions. Thus, this could suggest that undiagnosed ADPKD subjects, as predicted by our approach, could be relevant and will most likely require more clinical attention. Nevertheless, our estimation, in addition to the averaged ones derived from literature, not exceeding the limit of 5:10,000 inhabitants, are compatible with the definition of rare disease adopted by the European Medicines Agency and Food and Drug Administration.

• Aged
• Cohort Studies
• Europe/epidemiology
• Female
• Humans
• Male
• Middle Aged
• Polycystic Kidney, Autosomal Dominant/diagnosis
• Polycystic Kidney, Autosomal Dominant/epidemiology
• Prevalence

• Ministero della Salute

• ADPKD
• cystic kidney
• liver cysts
• polycystic kidney disease