Autosomal Dominant Polycystic Kidney Disease

Mendelian MONDO:0004691 Pathograph 15 Ciliopathy Kidney Cystic Disease Renal Tubular Disease

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem inherited renal tubular disease caused most often by pathogenic variants in PKD1 or PKD2 and less commonly by genes that perturb polycystin biogenesis or ciliary signaling. Loss or reduced dosage of the polycystin-1/polycystin-2 ciliary signaling complex in kidney epithelial cells disinhibits cilium-dependent cyst-promoting signals, reduces calcium signaling, increases cAMP-dependent proliferation and chloride-driven fluid secretion, and drives progressive renal cyst enlargement. Expanding cysts remodel and destroy renal parenchyma, leading to kidney enlargement, hypertension, chronic kidney disease, and frequently kidney failure; extrarenal cysts, especially hepatic cysts, and vascular complications such as intracranial aneurysm can also occur.

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1
Inheritance
6
Pathophys.
26
Phenotypes
15
Pathograph
9
Genes
2
Treatments
1
Trials
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
ADPKD is usually inherited from an affected parent, although de novo disease occurs in a minority of families.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (1 reference)
PMID:40126492 SUPPORT Human Clinical
"Most persons with ADPKD have an affected parent, but de novo disease is suggested in 10% to 25% of families."
This supports autosomal dominant familial transmission with occasional de novo disease.
⚙

Pathophysiology

6
Polycystin complex dosage loss at the renal primary cilium
The proximal defect is reduced activity or loss of the polycystin-1 and polycystin-2 complex in kidney epithelial primary cilia. PKD1 encodes polycystin-1 and PKD2 encodes polycystin-2; pathogenic variants or reduced polycystin dosage disturb the receptor-channel complex that normally helps maintain tubular architecture.
kidney epithelial cell link
PKD1 link PKD2 link
intracellular calcium ion homeostasis link ↓ DECREASED
primary cilium link
Downstream
Cilium-dependent cyst-promoting signal disinhibition Loss of functional polycystins removes tonic suppression of a cilium-dependent cyst-promoting signal.
Reduced calcium and increased cAMP signaling Functional loss of polycystin signaling reduces calcium signaling and raises cAMP, creating a proliferative and secretory cyst epithelium.
Show evidence (2 references)
PMID:26877954 SUPPORT Model Organism
"PC1 forms a complex with PC2 via their respective carboxy-terminal tails. Both proteins are expressed in the primary cilia. Mutations in either gene affect the normal architecture of renal tubules, giving rise to ADPKD."
The mechanistic review directly links the PKD1/PKD2 polycystin complex in primary cilia to renal tubule architecture and ADPKD.
PMID:40126492 SUPPORT Human Clinical
"ADPKD is typically diagnosed in individuals aged 27 to 42 years and is primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes."
This clinical review identifies PKD1 and PKD2 as the major causal genes.
Cilium-dependent cyst-promoting signal disinhibition
When polycystins are absent or under-dosed while cilia remain intact, a cilium-dependent signal that promotes cyst growth is no longer suppressed. This explains why cyst expansion depends on both polycystin loss and the persistence of intact ciliary signaling.
kidney epithelial cell link
primary cilium link
Downstream
Renal epithelial proliferation and fluid secretion Disinhibited cyst-promoting ciliary signals converge with cAMP/MAPK signaling to increase epithelial proliferation and secretion.
Show evidence (1 reference)
PMID:26877954 SUPPORT Model Organism
"PCs provide baseline tonic inhibition of a cilium-dependent signal that promotes cyst growth when unchecked following inactivation of PCs."
This directly supports the cilium-dependent cyst-promoting signal node.
Reduced calcium and increased cAMP signaling
Polycystin dysfunction reduces cellular calcium signaling and secondarily increases intracellular cAMP through altered adenylate cyclase and phosphodiesterase activity. Elevated cAMP activates protein kinase A and promotes both epithelial proliferation and chloride-driven fluid secretion.
kidney epithelial cell link
intracellular calcium ion homeostasis link ↓ DECREASED
Downstream
Renal epithelial proliferation and fluid secretion Increased cAMP/PKA signaling drives proliferation and chloride-dependent fluid secretion in cystic epithelium.
Show evidence (1 reference)
PMID:26877954 SUPPORT Model Organism
"This in turn results in increased adenylate cyclase and decreased phosphodiesterase activity, leading to increased levels of intracellular cAMP."
The snippet links reduced calcium signaling to increased intracellular cAMP.
Renal epithelial proliferation and fluid secretion
Cyst-lining epithelial cells proliferate excessively and secrete chloride and fluid into the cyst lumen, expanding epithelial-lined cysts and remodeling surrounding kidney tissue.
kidney epithelial cell link
epithelial cell proliferation link ↑ INCREASED chloride transmembrane transport link ↑ INCREASED
Downstream
Renal cyst expansion and kidney enlargement Proliferative, fluid-secreting epithelia expand renal cysts and enlarge the kidneys.
Show evidence (1 reference)
PMID:26877954 SUPPORT Model Organism
"ADPKD results from excessive proliferation of renal tubular epithelial cells and remodeling of surrounding structures, giving rise to growth of epithelial-lined cysts accompanied by fibrosis and accumulation of extracellular matrix."
This directly supports excessive tubular epithelial proliferation and tissue remodeling as cyst-growth mechanisms.
Renal cyst expansion and kidney enlargement
Progressive growth of numerous renal cysts increases total kidney volume and physically replaces or compresses functional kidney parenchyma.
kidney epithelial cell link
Downstream
Parenchymal destruction and progressive renal insufficiency Enlarging cysts destroy normal renal parenchyma and reduce kidney function over time.
Hypertension Progressive renal cyst burden and renal parenchymal injury contribute to the common hypertensive phenotype.
Show evidence (1 reference)
PMID:40126492 SUPPORT Human Clinical
"Patients with MIC 1C to MIC 1E have larger kidneys because of more rapid growth (6%-10% per year)"
The JAMA review links rapid kidney growth and total kidney volume to higher-risk ADPKD classes.
Parenchymal destruction and progressive renal insufficiency
Ongoing cyst expansion, fibrosis, and extracellular-matrix accumulation progressively reduce glomerular filtration, producing chronic kidney disease, elevated creatinine, and eventual kidney failure in many patients.
Downstream
Chronic kidney disease Loss of functional parenchyma manifests clinically as chronic kidney disease and declining eGFR.
Stage 5 chronic kidney disease Continued decline progresses to end-stage kidney disease in many affected individuals.
Show evidence (1 reference)
PMID:26877954 SUPPORT Model Organism
"As the disease progresses, this leads to destruction of the normal renal parenchyma, massive renal enlargement, deterioration of renal function, and eventually renal failure in >50% of affected individuals by late adulthood"
This directly supports the renal-function decline node.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Polycystic Kidney Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

26
Cardiovascular 3
Hypertension FREQUENT Hypertension (HP:0000822)
Show evidence (2 references)
ORPHA:730 SUPPORT Other
"HP:0000822 | Hypertension | Frequent (79-30%)"
Orphanet lists hypertension as frequent.
PMID:40126492 SUPPORT Human Clinical
"Hypertension affects 70% to 80% of patients with ADPKD"
The 2025 review quantitatively supports hypertension as a common feature.
Mitral valve prolapse OCCASIONAL Mitral valve prolapse (HP:0001634)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0001634 | Mitral valve prolapse | Occasional (29-5%)"
Orphanet lists mitral valve prolapse as occasional.
Aortic root aneurysm OCCASIONAL Aortic root aneurysm (HP:0002616)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0002616 | Aortic root aneurysm | Occasional (29-5%)"
Orphanet lists aortic root aneurysm as occasional.
Digestive 2
Hepatic cysts VERY_FREQUENT Hepatic cysts (HP:0001407)
Show evidence (2 references)
ORPHA:730 SUPPORT Other
"HP:0001407 | Hepatic cysts | Very frequent (99-80%)"
Orphanet lists hepatic cysts as very frequent.
PMID:40126492 SUPPORT Human Clinical
"More than 90% of patients older than 35 years have hepatic cysts"
The clinical review provides quantitative support for hepatic cysts as a very common extrarenal manifestation.
Pancreatic cysts OCCASIONAL Pancreatic cysts (HP:0001737)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0001737 | Pancreatic cysts | Occasional (29-5%)"
Orphanet lists pancreatic cysts as occasional.
Genitourinary 8
Renal cysts VERY_FREQUENT Renal cyst (HP:0000107)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0000107 | Renal cyst | Very frequent (99-80%)"
Orphanet lists renal cysts as very frequent in ADPKD.
Renal insufficiency VERY_FREQUENT Renal insufficiency (HP:0000083)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0000083 | Renal insufficiency | Very frequent (99-80%)"
Orphanet lists renal insufficiency as very frequent.
Hematuria FREQUENT Hematuria (HP:0000790)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0000790 | Hematuria | Frequent (79-30%)"
Orphanet lists hematuria as frequent.
Chronic kidney disease FREQUENT Chronic kidney disease (HP:0012622)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0012622 | Chronic kidney disease | Frequent (79-30%)"
Orphanet lists chronic kidney disease as frequent.
Stage 5 chronic kidney disease FREQUENT Stage 5 chronic kidney disease (HP:0003774)
Show evidence (2 references)
ORPHA:730 SUPPORT Other
"HP:0003774 | Stage 5 chronic kidney disease | Frequent (79-30%)"
Orphanet lists stage 5 chronic kidney disease as frequent.
PMID:40126492 SUPPORT Human Clinical
"Approximately 50% of individuals with ADPKD require kidney replacement therapy by 62 years of age."
This supports progression to kidney failure requiring replacement therapy in many patients.
Albuminuria FREQUENT Albuminuria (HP:0012592)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0012592 | Albuminuria | Frequent (79-30%)"
Orphanet lists albuminuria as frequent.
Enlarged kidney OCCASIONAL Enlarged kidney (HP:0000105)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0000105 | Enlarged kidney | Occasional (29-5%)"
Orphanet lists enlarged kidney as occasional.
Uric acid nephrolithiasis OCCASIONAL Uric acid nephrolithiasis (HP:0000791)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0000791 | Uric acid nephrolithiasis | Occasional (29-5%)"
Orphanet lists uric acid nephrolithiasis as occasional.
Metabolism 1
Elevated circulating creatinine concentration VERY_FREQUENT Elevated circulating creatinine concentration (HP:0003259)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0003259 | Elevated circulating creatinine concentration | Very frequent (99-80%)"
Orphanet lists elevated circulating creatinine as very frequent.
Constitutional 1
Flank pain FREQUENT Flank pain (HP:0030157)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0030157 | Flank pain | Frequent (79-30%)"
Orphanet lists flank pain as frequent.
Other 11
Decreased glomerular filtration rate VERY_FREQUENT Decreased glomerular filtration rate (HP:0012213)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0012213 | Decreased glomerular filtration rate | Very frequent (99-80%)"
Orphanet lists decreased GFR as very frequent.
Abnormal urinary electrolyte concentration FREQUENT Abnormal urinary electrolyte concentration (HP:0012591)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0012591 | Abnormal urinary electrolyte concentration | Frequent (79-30%)"
Orphanet lists this urinary electrolyte abnormality as frequent.
Recurrent urinary tract infections OCCASIONAL Recurrent urinary tract infections (HP:0000010)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0000010 | Recurrent urinary tract infections | Occasional (29-5%)"
Orphanet lists recurrent urinary tract infections as occasional.
Calcium oxalate nephrolithiasis OCCASIONAL Calcium oxalate nephrolithiasis (HP:0008672)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0008672 | Calcium oxalate nephrolithiasis | Occasional (29-5%)"
Orphanet lists calcium oxalate nephrolithiasis as occasional.
Pyelonephritis OCCASIONAL Pyelonephritis (HP:0012330)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0012330 | Pyelonephritis | Occasional (29-5%)"
Orphanet lists pyelonephritis as occasional.
Polycystic liver disease OCCASIONAL Polycystic liver disease (HP:0006557)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0006557 | Polycystic liver disease | Occasional (29-5%)"
Orphanet lists polycystic liver disease as occasional.
Cerebral arterial dilatation OCCASIONAL Dilatation of the cerebral artery (HP:0004944)
Show evidence (2 references)
ORPHA:730 SUPPORT Other
"HP:0004944 | Dilatation of the cerebral artery | Occasional (29-5%)"
Orphanet lists cerebral artery dilatation as occasional.
PMID:40126492 SUPPORT Human Clinical
"approximately 9% to 14% develop intracranial aneurysms"
The review quantifies intracranial aneurysm risk in ADPKD.
Abnormal systemic arterial morphology OCCASIONAL Abnormal systemic arterial morphology (HP:0011004)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0011004 | Abnormal systemic arterial morphology | Occasional (29-5%)"
Orphanet lists abnormal systemic arterial morphology as occasional.
Arachnoid cyst OCCASIONAL Arachnoid cyst (HP:0100702)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0100702 | Arachnoid cyst | Occasional (29-5%)"
Orphanet lists arachnoid cyst as occasional.
Pituitary growth hormone cell adenoma VERY_RARE Pituitary growth hormone cell adenoma (HP:0011760)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0011760 | Pituitary growth hormone cell adenoma | Very rare (<4-1%)"
Orphanet lists this pituitary adenoma as very rare.
Reduced sperm motility OCCASIONAL Reduced sperm motility (HP:0012207)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0012207 | Reduced sperm motility | Occasional (29-5%)"
Orphanet lists reduced sperm motility as occasional.
🧬

Genetic Associations

9
PKD1 pathogenic variants (CAUSATIVE)
Show evidence (3 references)
ORPHA:730 SUPPORT Other
"PKD1 | polycystin 1, transient receptor potential channel interacting | hgnc:9008 | Disease-causing germline mutation(s) in"
Orphanet lists PKD1 as a disease-causing gene.
PMID:40126492 SUPPORT Human Clinical
"primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes."
The review identifies PKD1 as the major causal gene.
CGGV:assertion_09d61dec-314b-4c5f-af2e-f22fc5992c12-2021-02-26T151356.823Z SUPPORT Other
"PKD1 | HGNC:9008 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
ClinGen classifies the PKD1-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
PKD2 pathogenic variants (CAUSATIVE)
Show evidence (3 references)
ORPHA:730 SUPPORT Other
"PKD2 | polycystin 2, transient receptor potential cation channel | hgnc:9009 | Disease-causing germline mutation(s) in"
Orphanet lists PKD2 as a disease-causing gene.
PMID:40126492 SUPPORT Human Clinical
"primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes."
The review identifies PKD2 as the second major causal gene.
CGGV:assertion_ae0ae123-be04-4ba2-b685-594ca47a3467-2023-12-08T170000.000Z SUPPORT Other
"PKD2 | HGNC:9009 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
ClinGen classifies the PKD2-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
GANAB pathogenic variants (CAUSATIVE)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"GANAB | glucosidase II alpha subunit | hgnc:4138 | Disease-causing germline mutation(s) in"
Orphanet lists GANAB as a disease-causing gene.
DNAJB11 pathogenic loss-of-function variants (CAUSATIVE)
Show evidence (2 references)
ORPHA:730 SUPPORT Other
"DNAJB11 | DnaJ heat shock protein family (Hsp40) member B11 | hgnc:14889 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists DNAJB11 loss-of-function variants as disease-causing.
CGGV:assertion_dbbe08a1-2f13-445d-9492-d1f070e66c0c-2023-10-25T160000.000Z SUPPORT Other
"DNAJB11 | HGNC:14889 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
ClinGen classifies the DNAJB11-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
IFT140 pathogenic loss-of-function variants (CAUSATIVE)
Show evidence (2 references)
ORPHA:730 SUPPORT Other
"IFT140 | intraflagellar transport 140 | hgnc:29077 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists IFT140 loss-of-function variants as disease-causing.
CGGV:assertion_40ced6e2-4d01-46b5-acd3-3964013add3b-2024-04-09T160000.000Z SUPPORT Other
"IFT140 | HGNC:29077 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
ClinGen classifies the IFT140-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
ALG5 pathogenic variants (CAUSATIVE)
Show evidence (2 references)
ORPHA:730 SUPPORT Other
"ALG5 | ALG5 dolichyl-phosphate beta-glucosyltransferase | hgnc:20266 | Disease-causing germline mutation(s) in"
Orphanet lists ALG5 as a disease-causing gene.
CGGV:assertion_1883b1e7-0fb2-4ad5-8ed3-515bf65dc11e-2023-03-22T160000.000Z SUPPORT Other
"ALG5 | HGNC:20266 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Moderate"
ClinGen classifies the ALG5-autosomal dominant polycystic kidney disease gene-disease relationship as moderate with autosomal dominant inheritance.
ALG9 pathogenic loss-of-function variants (CAUSATIVE)
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"ALG9 | ALG9 alpha-1,2-mannosyltransferase | hgnc:15672 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists ALG9 loss-of-function variants as disease-causing.
NEK8 pathogenic variants (CAUSATIVE)
Show evidence (2 references)
ORPHA:730 SUPPORT Other
"NEK8 | NIMA related kinase 8 | hgnc:13387 | Disease-causing germline mutation(s) in"
Orphanet lists NEK8 as a disease-causing gene.
CGGV:assertion_32e19522-798c-4c32-a1f7-0cc42660b510-2024-01-08T170000.000Z SUPPORT Other
"NEK8 | HGNC:13387 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Strong"
ClinGen classifies the NEK8-autosomal dominant polycystic kidney disease gene-disease relationship as strong with autosomal dominant inheritance.
ALG8 (Pathogenic Variants)
Show evidence (1 reference)
CGGV:assertion_13259bf6-e954-4159-b247-c9685638e537-2025-03-10T160000.000Z SUPPORT Other
"ALG8 | HGNC:23161 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
ClinGen classifies the ALG8-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
💊

Treatments

2
Tolvaptan vasopressin V2 receptor antagonist therapy
Action: Pharmacotherapy NCIT:C15986
Agent: tolvaptan ↗
Tolvaptan is disease-modifying pharmacotherapy for adults at high risk of rapid progression; by antagonizing vasopressin V2 signaling it reduces the annual rate of kidney-volume growth and slows kidney-function decline.
Mechanism Target:
INHIBITS Reduced calcium and increased cAMP signaling — Vasopressin V2 receptor antagonism lowers the cAMP drive that supports cyst epithelial proliferation and secretion.
Show evidence (1 reference)
PMID:23121377 SUPPORT Human Clinical
"Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function."
This supports the mechanistic rationale for tolvaptan targeting vasopressin-driven cyst growth.
Target Phenotypes: Renal cyst ↗ Decreased glomerular filtration rate ↗
Show evidence (2 references)
PMID:23121377 SUPPORT Human Clinical
"Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD"
The pivotal TEMPO 3:4 randomized trial supports tolvaptan as disease-modifying therapy.
PMID:40126492 SUPPORT Human Clinical
"The vasopressin type 2 receptor antagonist tolvaptan reduces the annual rate of eGFR decline by 0.98 to 1.27 mL/min/1.73 m2"
The 2025 review summarizes tolvaptan's effect on eGFR decline and its current indication.
Dietary sodium restriction and blood pressure targets
Action: dietary sodium intake avoidance MAXO:0010096
Management includes strict blood pressure targets and dietary sodium restriction to reduce cardiovascular and kidney-progression risk.
Target Phenotypes: Hypertension ↗ Chronic kidney disease ↗
Show evidence (2 references)
PMID:40126492 SUPPORT Human Clinical
"Optimal management of ADPKD includes systolic blood pressure lower than 120 mm Hg for most patients"
This supports blood pressure targets as a management component.
PMID:40126492 SUPPORT Human Clinical
"dietary sodium restriction (<2000 mg/d)"
This directly supports sodium restriction as a treatment component.
🔬

Biochemical Markers

2
Creatinine (INCREASED)
Context: Circulating creatinine increases as glomerular filtration declines.
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0003259 | Elevated circulating creatinine concentration | Very frequent (99-80%)"
Orphanet supports elevated creatinine as a very frequent laboratory feature.
Glomerular filtration rate (DECREASED)
Context: Declining eGFR is the central biomarker of progressive ADPKD kidney dysfunction.
Show evidence (1 reference)
ORPHA:730 SUPPORT Other
"HP:0012213 | Decreased glomerular filtration rate | Very frequent (99-80%)"
Orphanet supports decreased GFR as a very frequent laboratory feature.
🔬

Clinical Trials

1
NCT00428948 PHASE_III COMPLETED
TEMPO 3:4 was a phase 3 placebo-controlled trial evaluating oral tolvaptan in adults with ADPKD.
Target Phenotypes: Renal cyst ↗ Decreased glomerular filtration rate ↗
Show evidence (2 references)
clinicaltrials:NCT00428948 SUPPORT
"This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus placebo in patients with ADPKD."
ClinicalTrials.gov summarizes the tolvaptan efficacy and safety trial in ADPKD.
PMID:23121377 SUPPORT Human Clinical
"In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD"
The published TEMPO 3:4 trial confirms trial design and enrollment.
{ }

Source YAML

click to show 
name: Autosomal Dominant Polycystic Kidney Disease
creation_date: "2026-05-08T16:23:43Z"
updated_date: "2026-05-08T16:23:43Z"
category: Mendelian
description: >-
  Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem
  inherited renal tubular disease caused most often by pathogenic variants in
  PKD1 or PKD2 and less commonly by genes that perturb polycystin biogenesis or
  ciliary signaling. Loss or reduced dosage of the polycystin-1/polycystin-2
  ciliary signaling complex in kidney epithelial cells disinhibits
  cilium-dependent cyst-promoting signals, reduces calcium signaling, increases
  cAMP-dependent proliferation and chloride-driven fluid secretion, and drives
  progressive renal cyst enlargement. Expanding cysts remodel and destroy renal
  parenchyma, leading to kidney enlargement, hypertension, chronic kidney
  disease, and frequently kidney failure; extrarenal cysts, especially hepatic
  cysts, and vascular complications such as intracranial aneurysm can also
  occur.
disease_term:
  preferred_term: autosomal dominant polycystic kidney disease
  term:
    id: MONDO:0004691
    label: autosomal dominant polycystic kidney disease
synonyms:
- ADPKD
- adult polycystic kidney disease
- polycystic kidney disease, autosomal dominant
parents:
- Ciliopathy
- Kidney Cystic Disease
- Renal Tubular Disease
prevalence:
- population: United States
  percentage: 9.3 per 10,000
  evidence:
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ADPKD accounts for 5% to 10% of kidney failure in the US and Europe, and
      its prevalence in the US is 9.3 per 10 000 individuals.
    explanation: >-
      The 2025 clinical review provides a current US prevalence estimate and
      quantifies the contribution to kidney failure.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    ADPKD is usually inherited from an affected parent, although de novo disease
    occurs in a minority of families.
  evidence:
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most persons with ADPKD have an affected parent, but de novo disease is
      suggested in 10% to 25% of families.
    explanation: >-
      This supports autosomal dominant familial transmission with occasional de
      novo disease.
pathophysiology:
- name: Polycystin complex dosage loss at the renal primary cilium
  description: >-
    The proximal defect is reduced activity or loss of the polycystin-1 and
    polycystin-2 complex in kidney epithelial primary cilia. PKD1 encodes
    polycystin-1 and PKD2 encodes polycystin-2; pathogenic variants or reduced
    polycystin dosage disturb the receptor-channel complex that normally helps
    maintain tubular architecture.
  genes:
  - preferred_term: PKD1
    term:
      id: hgnc:9008
      label: PKD1
  - preferred_term: PKD2
    term:
      id: hgnc:9009
      label: PKD2
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  biological_processes:
  - preferred_term: intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:26877954
    reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      PC1 forms a complex with PC2 via their respective carboxy-terminal tails.
      Both proteins are expressed in the primary cilia. Mutations in either
      gene affect the normal architecture of renal tubules, giving rise to
      ADPKD.
    explanation: >-
      The mechanistic review directly links the PKD1/PKD2 polycystin complex
      in primary cilia to renal tubule architecture and ADPKD.
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ADPKD is typically diagnosed in individuals aged 27 to 42 years and is
      primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%)
      genes.
    explanation: >-
      This clinical review identifies PKD1 and PKD2 as the major causal genes.
  downstream:
  - target: Cilium-dependent cyst-promoting signal disinhibition
    description: >-
      Loss of functional polycystins removes tonic suppression of a
      cilium-dependent cyst-promoting signal.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26877954
      reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        cilia-dependent, cyst-promoting pathway that is normally repressed by
        polycystin function.
      explanation: >-
        This supports the downstream disinhibition model.
  - target: Reduced calcium and increased cAMP signaling
    description: >-
      Functional loss of polycystin signaling reduces calcium signaling and
      raises cAMP, creating a proliferative and secretory cyst epithelium.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26877954
      reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Functional loss of PC1 at the cilium results in reduced cellular
        calcium signaling
      explanation: >-
        The review links polycystin loss at the cilium to reduced cellular
        calcium signaling.
- name: Cilium-dependent cyst-promoting signal disinhibition
  description: >-
    When polycystins are absent or under-dosed while cilia remain intact, a
    cilium-dependent signal that promotes cyst growth is no longer suppressed.
    This explains why cyst expansion depends on both polycystin loss and the
    persistence of intact ciliary signaling.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0005929
      label: cilium
  evidence:
  - reference: PMID:26877954
    reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      PCs provide baseline tonic inhibition of a cilium-dependent signal that
      promotes cyst growth when unchecked following inactivation of PCs.
    explanation: >-
      This directly supports the cilium-dependent cyst-promoting signal node.
  downstream:
  - target: Renal epithelial proliferation and fluid secretion
    description: >-
      Disinhibited cyst-promoting ciliary signals converge with cAMP/MAPK
      signaling to increase epithelial proliferation and secretion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26877954
      reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        increased activity of both the MAPK/ERK and cAMP pathways in cystic
        mice
      explanation: >-
        This supports MAPK/ERK and cAMP pathway activity downstream of cystic
        polycystin/cilium signaling.
- name: Reduced calcium and increased cAMP signaling
  description: >-
    Polycystin dysfunction reduces cellular calcium signaling and secondarily
    increases intracellular cAMP through altered adenylate cyclase and
    phosphodiesterase activity. Elevated cAMP activates protein kinase A and
    promotes both epithelial proliferation and chloride-driven fluid secretion.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:26877954
    reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This in turn results in increased adenylate cyclase and decreased
      phosphodiesterase activity, leading to increased levels of intracellular
      cAMP.
    explanation: >-
      The snippet links reduced calcium signaling to increased intracellular
      cAMP.
  downstream:
  - target: Renal epithelial proliferation and fluid secretion
    description: >-
      Increased cAMP/PKA signaling drives proliferation and chloride-dependent
      fluid secretion in cystic epithelium.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26877954
      reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Increased cAMP in cystic epithelium increases the activity of protein
        kinase A, which can result in increased cell proliferation and
        chloride-driven fluid secretion; features associated with cyst growth
      explanation: >-
        This directly supports proliferation and chloride-driven secretion as
        cAMP/PKA-mediated cyst-growth features.
- name: Renal epithelial proliferation and fluid secretion
  description: >-
    Cyst-lining epithelial cells proliferate excessively and secrete chloride
    and fluid into the cyst lumen, expanding epithelial-lined cysts and
    remodeling surrounding kidney tissue.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: epithelial cell proliferation
    term:
      id: GO:0050673
      label: epithelial cell proliferation
    modifier: INCREASED
  - preferred_term: chloride transmembrane transport
    term:
      id: GO:1902476
      label: chloride transmembrane transport
    modifier: INCREASED
  evidence:
  - reference: PMID:26877954
    reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      ADPKD results from excessive proliferation of renal tubular epithelial
      cells and remodeling of surrounding structures, giving rise to growth of
      epithelial-lined cysts accompanied by fibrosis and accumulation of
      extracellular matrix.
    explanation: >-
      This directly supports excessive tubular epithelial proliferation and
      tissue remodeling as cyst-growth mechanisms.
  downstream:
  - target: Renal cyst expansion and kidney enlargement
    description: >-
      Proliferative, fluid-secreting epithelia expand renal cysts and enlarge
      the kidneys.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26718155
      reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Path Forward."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The typical renal phenotype of ADPKD is the insidious development of
        hundreds of renal cysts, which form in childhood and grow progressively
        through life
      explanation: >-
        This supports progressive renal cyst expansion as the downstream
        phenotype.
- name: Renal cyst expansion and kidney enlargement
  description: >-
    Progressive growth of numerous renal cysts increases total kidney volume
    and physically replaces or compresses functional kidney parenchyma.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  evidence:
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with MIC 1C to MIC 1E have larger kidneys because of more rapid
      growth (6%-10% per year)
    explanation: >-
      The JAMA review links rapid kidney growth and total kidney volume to
      higher-risk ADPKD classes.
  downstream:
  - target: Parenchymal destruction and progressive renal insufficiency
    description: >-
      Enlarging cysts destroy normal renal parenchyma and reduce kidney
      function over time.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26877954
      reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        this leads to destruction of the normal renal parenchyma, massive renal
        enlargement, deterioration of renal function, and eventually renal
        failure
      explanation: >-
        This directly links cyst enlargement to parenchymal destruction and
        renal failure.
  - target: Hypertension
    description: >-
      Progressive renal cyst burden and renal parenchymal injury contribute to
      the common hypertensive phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40126492
      reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hypertension affects 70% to 80% of patients with ADPKD
      explanation: >-
        The review supports hypertension as a common downstream clinical
        feature of ADPKD.
- name: Parenchymal destruction and progressive renal insufficiency
  description: >-
    Ongoing cyst expansion, fibrosis, and extracellular-matrix accumulation
    progressively reduce glomerular filtration, producing chronic kidney
    disease, elevated creatinine, and eventual kidney failure in many patients.
  evidence:
  - reference: PMID:26877954
    reference_title: "Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As the disease progresses, this leads to destruction of the normal renal
      parenchyma, massive renal enlargement, deterioration of renal function,
      and eventually renal failure in >50% of affected individuals by late
      adulthood
    explanation: >-
      This directly supports the renal-function decline node.
  downstream:
  - target: Chronic kidney disease
    description: >-
      Loss of functional parenchyma manifests clinically as chronic kidney
      disease and declining eGFR.
    causal_link_type: DIRECT
  - target: Stage 5 chronic kidney disease
    description: >-
      Continued decline progresses to end-stage kidney disease in many
      affected individuals.
    causal_link_type: DIRECT
phenotypes:
- category: Renal
  name: Renal cysts
  frequency: VERY_FREQUENT
  description: >-
    Fluid-filled renal epithelial cysts are the defining structural feature of
    ADPKD.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000107 | Renal cyst | Very frequent (99-80%)"
    explanation: Orphanet lists renal cysts as very frequent in ADPKD.
- category: Renal
  name: Renal insufficiency
  frequency: VERY_FREQUENT
  description: >-
    Progressive cyst growth and parenchymal destruction reduce renal function.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000083 | Renal insufficiency | Very frequent (99-80%)"
    explanation: Orphanet lists renal insufficiency as very frequent.
- category: Renal
  name: Decreased glomerular filtration rate
  frequency: VERY_FREQUENT
  description: >-
    Declining glomerular filtration rate is a key measurable manifestation of
    ADPKD progression.
  phenotype_term:
    preferred_term: Decreased glomerular filtration rate
    term:
      id: HP:0012213
      label: Decreased glomerular filtration rate
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012213 | Decreased glomerular filtration rate | Very frequent (99-80%)"
    explanation: Orphanet lists decreased GFR as very frequent.
- category: Laboratory
  name: Elevated circulating creatinine concentration
  frequency: VERY_FREQUENT
  description: >-
    Creatinine rises as kidney function declines.
  phenotype_term:
    preferred_term: Elevated circulating creatinine concentration
    term:
      id: HP:0003259
      label: Elevated circulating creatinine concentration
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003259 | Elevated circulating creatinine concentration | Very frequent (99-80%)"
    explanation: Orphanet lists elevated circulating creatinine as very frequent.
- category: Hepatic
  name: Hepatic cysts
  frequency: VERY_FREQUENT
  description: >-
    Hepatic cysts are the most frequent extrarenal cystic manifestation of
    ADPKD.
  phenotype_term:
    preferred_term: Hepatic cysts
    term:
      id: HP:0001407
      label: Hepatic cysts
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001407 | Hepatic cysts | Very frequent (99-80%)"
    explanation: Orphanet lists hepatic cysts as very frequent.
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 90% of patients older than 35 years have hepatic cysts
    explanation: >-
      The clinical review provides quantitative support for hepatic cysts as a
      very common extrarenal manifestation.
- category: Cardiovascular
  name: Hypertension
  frequency: FREQUENT
  description: >-
    Hypertension is common and is a major modifiable risk factor in ADPKD.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000822 | Hypertension | Frequent (79-30%)"
    explanation: Orphanet lists hypertension as frequent.
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertension affects 70% to 80% of patients with ADPKD
    explanation: >-
      The 2025 review quantitatively supports hypertension as a common feature.
- category: Renal
  name: Hematuria
  frequency: FREQUENT
  description: >-
    Hematuria occurs in ADPKD, often related to cyst hemorrhage, stones, or
    infection.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000790 | Hematuria | Frequent (79-30%)"
    explanation: Orphanet lists hematuria as frequent.
- category: Renal
  name: Chronic kidney disease
  frequency: FREQUENT
  description: >-
    Progressive renal cyst burden produces chronic kidney disease.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012622 | Chronic kidney disease | Frequent (79-30%)"
    explanation: Orphanet lists chronic kidney disease as frequent.
- category: Renal
  name: Stage 5 chronic kidney disease
  frequency: FREQUENT
  description: >-
    A substantial fraction of patients progress to end-stage kidney disease.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003774 | Stage 5 chronic kidney disease | Frequent (79-30%)"
    explanation: Orphanet lists stage 5 chronic kidney disease as frequent.
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 50% of individuals with ADPKD require kidney replacement
      therapy by 62 years of age.
    explanation: >-
      This supports progression to kidney failure requiring replacement
      therapy in many patients.
- category: Renal
  name: Flank pain
  frequency: FREQUENT
  description: >-
    Flank or abdominal pain may reflect kidney enlargement, cyst hemorrhage,
    stones, or infection.
  phenotype_term:
    preferred_term: Flank pain
    term:
      id: HP:0030157
      label: Flank pain
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030157 | Flank pain | Frequent (79-30%)"
    explanation: Orphanet lists flank pain as frequent.
- category: Laboratory
  name: Albuminuria
  frequency: FREQUENT
  description: >-
    Albuminuria is a frequent urinary abnormality in ADPKD.
  phenotype_term:
    preferred_term: Albuminuria
    term:
      id: HP:0012592
      label: Albuminuria
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012592 | Albuminuria | Frequent (79-30%)"
    explanation: Orphanet lists albuminuria as frequent.
- category: Laboratory
  name: Abnormal urinary electrolyte concentration
  frequency: FREQUENT
  description: >-
    Abnormal urinary electrolyte handling is a frequent laboratory feature of
    ADPKD.
  phenotype_term:
    preferred_term: Abnormal urinary electrolyte concentration
    term:
      id: HP:0012591
      label: Abnormal urinary electrolyte concentration
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012591 | Abnormal urinary electrolyte concentration | Frequent (79-30%)"
    explanation: Orphanet lists this urinary electrolyte abnormality as frequent.
- category: Infectious
  name: Recurrent urinary tract infections
  frequency: OCCASIONAL
  description: >-
    Urinary tract infections occur in a subset of patients.
  phenotype_term:
    preferred_term: Recurrent urinary tract infections
    term:
      id: HP:0000010
      label: Recurrent urinary tract infections
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000010 | Recurrent urinary tract infections | Occasional (29-5%)"
    explanation: Orphanet lists recurrent urinary tract infections as occasional.
- category: Renal
  name: Enlarged kidney
  frequency: OCCASIONAL
  description: >-
    Progressive cyst burden can cause radiographic or palpable kidney
    enlargement.
  phenotype_term:
    preferred_term: Enlarged kidney
    term:
      id: HP:0000105
      label: Enlarged kidney
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000105 | Enlarged kidney | Occasional (29-5%)"
    explanation: Orphanet lists enlarged kidney as occasional.
- category: Renal
  name: Uric acid nephrolithiasis
  frequency: OCCASIONAL
  description: >-
    Uric acid kidney stones occur in a subset of affected individuals.
  phenotype_term:
    preferred_term: Uric acid nephrolithiasis
    term:
      id: HP:0000791
      label: Uric acid nephrolithiasis
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000791 | Uric acid nephrolithiasis | Occasional (29-5%)"
    explanation: Orphanet lists uric acid nephrolithiasis as occasional.
- category: Renal
  name: Calcium oxalate nephrolithiasis
  frequency: OCCASIONAL
  description: >-
    Calcium oxalate stones are another reported nephrolithiasis subtype.
  phenotype_term:
    preferred_term: Calcium oxalate nephrolithiasis
    term:
      id: HP:0008672
      label: Calcium oxalate nephrolithiasis
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008672 | Calcium oxalate nephrolithiasis | Occasional (29-5%)"
    explanation: Orphanet lists calcium oxalate nephrolithiasis as occasional.
- category: Infectious
  name: Pyelonephritis
  frequency: OCCASIONAL
  description: >-
    Pyelonephritis can complicate ADPKD.
  phenotype_term:
    preferred_term: Pyelonephritis
    term:
      id: HP:0012330
      label: Pyelonephritis
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012330 | Pyelonephritis | Occasional (29-5%)"
    explanation: Orphanet lists pyelonephritis as occasional.
- category: Hepatic
  name: Polycystic liver disease
  frequency: OCCASIONAL
  description: >-
    Some patients develop a broader polycystic liver disease phenotype beyond
    isolated hepatic cysts.
  phenotype_term:
    preferred_term: Polycystic liver disease
    term:
      id: HP:0006557
      label: Polycystic liver disease
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006557 | Polycystic liver disease | Occasional (29-5%)"
    explanation: Orphanet lists polycystic liver disease as occasional.
- category: Gastrointestinal
  name: Pancreatic cysts
  frequency: OCCASIONAL
  description: >-
    Pancreatic cysts are an occasional extrarenal cystic feature.
  phenotype_term:
    preferred_term: Pancreatic cysts
    term:
      id: HP:0001737
      label: Pancreatic cysts
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001737 | Pancreatic cysts | Occasional (29-5%)"
    explanation: Orphanet lists pancreatic cysts as occasional.
- category: Cardiovascular
  name: Mitral valve prolapse
  frequency: OCCASIONAL
  description: >-
    Mitral valve prolapse is a recognized occasional cardiovascular
    manifestation.
  phenotype_term:
    preferred_term: Mitral valve prolapse
    term:
      id: HP:0001634
      label: Mitral valve prolapse
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001634 | Mitral valve prolapse | Occasional (29-5%)"
    explanation: Orphanet lists mitral valve prolapse as occasional.
- category: Cardiovascular
  name: Aortic root aneurysm
  frequency: OCCASIONAL
  description: >-
    Aortic root aneurysm is an occasional vascular manifestation.
  phenotype_term:
    preferred_term: Aortic root aneurysm
    term:
      id: HP:0002616
      label: Aortic root aneurysm
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002616 | Aortic root aneurysm | Occasional (29-5%)"
    explanation: Orphanet lists aortic root aneurysm as occasional.
- category: Neurologic
  name: Cerebral arterial dilatation
  frequency: OCCASIONAL
  description: >-
    Intracranial aneurysm and related cerebral arterial dilatation are important
    ADPKD vascular complications.
  phenotype_term:
    preferred_term: Dilatation of the cerebral artery
    term:
      id: HP:0004944
      label: Dilatation of the cerebral artery
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004944 | Dilatation of the cerebral artery | Occasional (29-5%)"
    explanation: Orphanet lists cerebral artery dilatation as occasional.
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      approximately 9% to 14% develop intracranial aneurysms
    explanation: >-
      The review quantifies intracranial aneurysm risk in ADPKD.
- category: Cardiovascular
  name: Abnormal systemic arterial morphology
  frequency: OCCASIONAL
  description: >-
    ADPKD includes occasional systemic vascular structural abnormalities.
  phenotype_term:
    preferred_term: Abnormal systemic arterial morphology
    term:
      id: HP:0011004
      label: Abnormal systemic arterial morphology
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011004 | Abnormal systemic arterial morphology | Occasional (29-5%)"
    explanation: Orphanet lists abnormal systemic arterial morphology as occasional.
- category: Neurologic
  name: Arachnoid cyst
  frequency: OCCASIONAL
  description: >-
    Arachnoid cysts are occasional extrarenal cystic manifestations.
  phenotype_term:
    preferred_term: Arachnoid cyst
    term:
      id: HP:0100702
      label: Arachnoid cyst
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100702 | Arachnoid cyst | Occasional (29-5%)"
    explanation: Orphanet lists arachnoid cyst as occasional.
- category: Endocrine
  name: Pituitary growth hormone cell adenoma
  frequency: VERY_RARE
  description: >-
    Orphanet records pituitary growth hormone cell adenoma as a very rare
    association.
  phenotype_term:
    preferred_term: Pituitary growth hormone cell adenoma
    term:
      id: HP:0011760
      label: Pituitary growth hormone cell adenoma
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011760 | Pituitary growth hormone cell adenoma | Very rare (<4-1%)"
    explanation: Orphanet lists this pituitary adenoma as very rare.
- category: Reproductive
  name: Reduced sperm motility
  frequency: OCCASIONAL
  description: >-
    Reduced sperm motility is an occasional reproductive manifestation.
  phenotype_term:
    preferred_term: Reduced sperm motility
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012207 | Reduced sperm motility | Occasional (29-5%)"
    explanation: Orphanet lists reduced sperm motility as occasional.
biochemical:
- name: Creatinine
  presence: INCREASED
  context: >-
    Circulating creatinine increases as glomerular filtration declines.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003259 | Elevated circulating creatinine concentration | Very frequent (99-80%)"
    explanation: Orphanet supports elevated creatinine as a very frequent laboratory feature.
- name: Glomerular filtration rate
  presence: DECREASED
  context: >-
    Declining eGFR is the central biomarker of progressive ADPKD kidney
    dysfunction.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012213 | Decreased glomerular filtration rate | Very frequent (99-80%)"
    explanation: Orphanet supports decreased GFR as a very frequent laboratory feature.
genetic:
- name: PKD1 pathogenic variants
  gene_term:
    preferred_term: PKD1
    term:
      id: hgnc:9008
      label: PKD1
  association: CAUSATIVE
  features: >-
    PKD1 is the most common ADPKD gene and accounts for the majority of
    clinically ascertained disease.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PKD1 | polycystin 1, transient receptor potential channel interacting | hgnc:9008 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists PKD1 as a disease-causing gene.
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%)
      genes.
    explanation: The review identifies PKD1 as the major causal gene.
  - reference: CGGV:assertion_09d61dec-314b-4c5f-af2e-f22fc5992c12-2021-02-26T151356.823Z
    reference_title: "PKD1 / autosomal dominant polycystic kidney disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PKD1 | HGNC:9008 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
    explanation: ClinGen classifies the PKD1-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
- name: PKD2 pathogenic variants
  gene_term:
    preferred_term: PKD2
    term:
      id: hgnc:9009
      label: PKD2
  association: CAUSATIVE
  features: >-
    PKD2 is the second major ADPKD gene and encodes the calcium-permeable
    polycystin-2 channel.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PKD2 | polycystin 2, transient receptor potential cation channel | hgnc:9009 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists PKD2 as a disease-causing gene.
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%)
      genes.
    explanation: The review identifies PKD2 as the second major causal gene.
  - reference: CGGV:assertion_ae0ae123-be04-4ba2-b685-594ca47a3467-2023-12-08T170000.000Z
    reference_title: "PKD2 / autosomal dominant polycystic kidney disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PKD2 | HGNC:9009 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
    explanation: ClinGen classifies the PKD2-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
- name: GANAB pathogenic variants
  gene_term:
    preferred_term: GANAB
    term:
      id: hgnc:4138
      label: GANAB
  association: CAUSATIVE
  features: >-
    GANAB is an ADPKD-spectrum gene involved in glycoprotein processing and
    polycystin maturation.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GANAB | glucosidase II alpha subunit | hgnc:4138 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists GANAB as a disease-causing gene.
- name: DNAJB11 pathogenic loss-of-function variants
  gene_term:
    preferred_term: DNAJB11
    term:
      id: hgnc:14889
      label: DNAJB11
  association: CAUSATIVE
  features: >-
    DNAJB11 loss of function is a rarer ADPKD-spectrum cause with atypical
    cystic kidney disease.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DNAJB11 | DnaJ heat shock protein family (Hsp40) member B11 | hgnc:14889 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists DNAJB11 loss-of-function variants as disease-causing.
  - reference: CGGV:assertion_dbbe08a1-2f13-445d-9492-d1f070e66c0c-2023-10-25T160000.000Z
    reference_title: "DNAJB11 / autosomal dominant polycystic kidney disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DNAJB11 | HGNC:14889 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
    explanation: ClinGen classifies the DNAJB11-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
- name: IFT140 pathogenic loss-of-function variants
  gene_term:
    preferred_term: IFT140
    term:
      id: hgnc:29077
      label: IFT140
  association: CAUSATIVE
  features: >-
    IFT140 loss of function links ADPKD-spectrum disease to intraflagellar
    transport and ciliary biology.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IFT140 | intraflagellar transport 140 | hgnc:29077 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists IFT140 loss-of-function variants as disease-causing.
  - reference: CGGV:assertion_40ced6e2-4d01-46b5-acd3-3964013add3b-2024-04-09T160000.000Z
    reference_title: "IFT140 / autosomal dominant polycystic kidney disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IFT140 | HGNC:29077 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
    explanation: ClinGen classifies the IFT140-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
- name: ALG5 pathogenic variants
  gene_term:
    preferred_term: ALG5
    term:
      id: hgnc:20266
      label: ALG5
  association: CAUSATIVE
  features: >-
    ALG5 is a rare ADPKD-spectrum gene involved in glycosylation.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALG5 | ALG5 dolichyl-phosphate beta-glucosyltransferase | hgnc:20266 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists ALG5 as a disease-causing gene.
  - reference: CGGV:assertion_1883b1e7-0fb2-4ad5-8ed3-515bf65dc11e-2023-03-22T160000.000Z
    reference_title: "ALG5 / autosomal dominant polycystic kidney disease (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALG5 | HGNC:20266 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Moderate"
    explanation: ClinGen classifies the ALG5-autosomal dominant polycystic kidney disease gene-disease relationship as moderate with autosomal dominant inheritance.
- name: ALG9 pathogenic loss-of-function variants
  gene_term:
    preferred_term: ALG9
    term:
      id: hgnc:15672
      label: ALG9
  association: CAUSATIVE
  features: >-
    ALG9 loss of function is a rare ADPKD-spectrum cause involving
    glycosylation.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALG9 | ALG9 alpha-1,2-mannosyltransferase | hgnc:15672 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists ALG9 loss-of-function variants as disease-causing.
- name: NEK8 pathogenic variants
  gene_term:
    preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  association: CAUSATIVE
  features: >-
    NEK8 is a rare ADPKD-spectrum gene linked to ciliary signaling.
  evidence:
  - reference: ORPHA:730
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NEK8 | NIMA related kinase 8 | hgnc:13387 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists NEK8 as a disease-causing gene.
  - reference: CGGV:assertion_32e19522-798c-4c32-a1f7-0cc42660b510-2024-01-08T170000.000Z
    reference_title: "NEK8 / autosomal dominant polycystic kidney disease (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NEK8 | HGNC:13387 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Strong"
    explanation: ClinGen classifies the NEK8-autosomal dominant polycystic kidney disease gene-disease relationship as strong with autosomal dominant inheritance.
- name: ALG8
  gene_term:
    preferred_term: ALG8
    term:
      id: hgnc:23161
      label: ALG8
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_13259bf6-e954-4159-b247-c9685638e537-2025-03-10T160000.000Z
    reference_title: "ALG8 / autosomal dominant polycystic kidney disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALG8 | HGNC:23161 | autosomal dominant polycystic kidney disease | MONDO:0004691 | AD | Definitive"
    explanation: ClinGen classifies the ALG8-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Tolvaptan vasopressin V2 receptor antagonist therapy
  description: >-
    Tolvaptan is disease-modifying pharmacotherapy for adults at high risk of
    rapid progression; by antagonizing vasopressin V2 signaling it reduces the
    annual rate of kidney-volume growth and slows kidney-function decline.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tolvaptan
      term:
        id: CHEBI:32246
        label: tolvaptan
  target_phenotypes:
  - preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  - preferred_term: Decreased glomerular filtration rate
    term:
      id: HP:0012213
      label: Decreased glomerular filtration rate
  target_mechanisms:
  - target: Reduced calcium and increased cAMP signaling
    treatment_effect: INHIBITS
    description: >-
      Vasopressin V2 receptor antagonism lowers the cAMP drive that supports
      cyst epithelial proliferation and secretion.
    evidence:
    - reference: PMID:23121377
      reference_title: "Tolvaptan in patients with autosomal dominant polycystic kidney disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Preclinical studies indicated that vasopressin V(2)-receptor
        antagonists inhibit cyst growth and slow the decline of kidney function.
      explanation: >-
        This supports the mechanistic rationale for tolvaptan targeting
        vasopressin-driven cyst growth.
  evidence:
  - reference: PMID:23121377
    reference_title: "Tolvaptan in patients with autosomal dominant polycystic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tolvaptan, as compared with placebo, slowed the increase in total kidney
      volume and the decline in kidney function over a 3-year period in
      patients with ADPKD
    explanation: >-
      The pivotal TEMPO 3:4 randomized trial supports tolvaptan as
      disease-modifying therapy.
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The vasopressin type 2 receptor antagonist tolvaptan reduces the annual
      rate of eGFR decline by 0.98 to 1.27 mL/min/1.73 m2
    explanation: >-
      The 2025 review summarizes tolvaptan's effect on eGFR decline and its
      current indication.
- name: Dietary sodium restriction and blood pressure targets
  description: >-
    Management includes strict blood pressure targets and dietary sodium
    restriction to reduce cardiovascular and kidney-progression risk.
  treatment_term:
    preferred_term: dietary sodium intake avoidance
    term:
      id: MAXO:0010096
      label: dietary sodium intake avoidance
  target_phenotypes:
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Optimal management of ADPKD includes systolic blood pressure lower than
      120 mm Hg for most patients
    explanation: >-
      This supports blood pressure targets as a management component.
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dietary sodium restriction (<2000 mg/d)"
    explanation: >-
      This directly supports sodium restriction as a treatment component.
diagnosis:
- name: MRI total kidney volume risk stratification
  description: >-
    Height-adjusted total kidney volume by MRI is used in the Mayo Imaging
    Classification to stratify progression risk and guide tolvaptan candidacy.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  evidence:
  - reference: PMID:40126492
    reference_title: "Autosomal Dominant Polycystic Kidney Disease: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity of kidney disease can be quantified using the Mayo Imaging
      Classification (MIC), which stratifies patients based on total kidney
      volume adjusted for height and age
    explanation: >-
      This supports total kidney volume imaging for ADPKD risk stratification.
clinical_trials:
- name: NCT00428948
  phase: PHASE_III
  status: COMPLETED
  description: >-
    TEMPO 3:4 was a phase 3 placebo-controlled trial evaluating oral tolvaptan
    in adults with ADPKD.
  target_phenotypes:
  - preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  - preferred_term: Decreased glomerular filtration rate
    term:
      id: HP:0012213
      label: Decreased glomerular filtration rate
  evidence:
  - reference: clinicaltrials:NCT00428948
    supports: SUPPORT
    snippet: "This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus placebo in patients with ADPKD."
    explanation: >-
      ClinicalTrials.gov summarizes the tolvaptan efficacy and safety trial in
      ADPKD.
  - reference: PMID:23121377
    reference_title: "Tolvaptan in patients with autosomal dominant polycystic kidney disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this phase 3, multicenter, double-blind, placebo-controlled, 3-year
      trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had
      ADPKD
    explanation: >-
      The published TEMPO 3:4 trial confirms trial design and enrollment.
datasets: []
notes: >-
  Falcon and OpenAI deep-research provider attempts were started for this
  target but remained silent beyond a bounded wait and were terminated before
  output was produced. Curation proceeded from ORPHA:730 plus manually fetched
  PubMed and ClinicalTrials.gov evidence caches; provider failures and the
  literature scope are documented in the fallback research artifact.
📚

References & Deep Research

Deep Research

1
Autosomal Dominant Polycystic Kidney Disease Deep Research Fallback ▸

Autosomal Dominant Polycystic Kidney Disease Deep Research Fallback

Provider Attempts

  • 2026-05-08T16:24Z: Falcon deep-research was invoked directly with deep-research-client research for Autosomal dominant polycystic kidney disease (MONDO:0004691) because just research-disorder requires an existing YAML file. The command produced no output for approximately two minutes and was terminated.
  • 2026-05-08T16:27Z: OpenAI deep-research fallback was invoked with the same template and variables. The command produced no output for approximately 90 seconds and was terminated.

No provider-generated deep-research artifact was available. Curation therefore proceeded from exact, locally cached evidence and the structured ORPHA:730 record. No references_cache/*.md files were hand-created or hand-edited.

Evidence Scope Used For Curation

  • ORPHA:730 — structured Orphanet record for Autosomal dominant polycystic kidney disease. Used for the exact MONDO mapping, disease definition, disease-causing gene rows, and HPO phenotype-frequency rows.
  • PMID:40126492 — 2025 JAMA clinical review. Used for current prevalence, causal-gene proportions, major clinical frequencies (hepatic cysts, hypertension, intracranial aneurysm), progression to kidney replacement therapy, Mayo Imaging Classification, blood-pressure/sodium management, and tolvaptan effect size.
  • PMID:26718155 — clinical/pathogenesis review. Used for the PKD1/PKD2 loss-of-function framing and progressive renal-cyst phenotype.
  • PMID:26877954 — full-text mechanistic review on cyst growth, polycystins, and primary cilia. Used for the main pathophysiology chain: polycystin dosage loss at renal epithelial primary cilia, cilium-dependent cyst-promoting signal disinhibition, reduced calcium/increased cAMP signaling, epithelial proliferation, chloride-driven secretion, cyst expansion, fibrosis, parenchymal destruction, and renal failure.
  • PMID:23121377 / clinicaltrials:NCT00428948 — TEMPO 3:4 phase 3 tolvaptan trial. Used for the tolvaptan treatment entry, mechanism target, outcome evidence, and clinical-trial section.
  • PMID:16932388, PMID:10926175, and PMID:35253003 were reviewed as background scope for primary cilia, calcium homeostasis, Wnt/cAMP/Ras/MAPK signaling, two-hit pathogenesis, and JNK signaling, but were not cited directly in the YAML because the main cilium/cAMP pathway and clinical management claims were better supported by PMID:26877954, PMID:40126492, and PMID:23121377.

Curation Conclusions

ADPKD is best modeled as a renal epithelial ciliopathy in which reduced dosage or loss of PKD1/PKD2 polycystins and rarer polycystin-biogenesis/ciliary genes disrupt the polycystin receptor-channel complex at the primary cilium. The proximal consequence is loss of tonic suppression of a cilium-dependent cyst-promoting signal, accompanied by reduced cellular calcium signaling and increased intracellular cAMP. Elevated cAMP activates protein kinase A and supports epithelial proliferation plus chloride-driven fluid secretion, expanding epithelial-lined renal cysts. Progressive cyst expansion produces massive kidney enlargement, fibrosis/extracellular-matrix accumulation, destruction of renal parenchyma, declining GFR, elevated creatinine, chronic kidney disease, and kidney failure.

The curation prioritizes the major Orphanet clinical features: very frequent renal cysts, renal insufficiency, decreased GFR, elevated creatinine, and hepatic cysts; frequent hypertension, hematuria, chronic kidney disease, stage 5 chronic kidney disease, flank pain, albuminuria, and urinary electrolyte abnormalities; and clinically important occasional extrarenal/vascular features including nephrolithiasis, pyelonephritis, pancreatic cysts, mitral valve prolapse, aortic root aneurysm, cerebral artery dilatation/intracranial aneurysm, arachnoid cyst, and reproductive findings.

Treatment is represented by disease-modifying tolvaptan pharmacotherapy targeting the vasopressin/cAMP cyst-growth pathway, plus sodium restriction and blood-pressure targets as conservative management. Diagnosis is represented by MRI total-kidney-volume risk stratification through the Mayo Imaging Classification.