Autosomal Dominant Polycystic Kidney Disease

Mendelian MONDO:0004691 Pathograph 61 Show in embeddings browser Ciliopathy Kidney Cystic Disease Renal Tubular Disease

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited multisystem disorder, most often caused by PKD1 or PKD2 variants, with progressive renal epithelial cysts, frequent liver cysts and vascular complications. Reduced polycystin function permits cyst-promoting ciliary signaling; cAMP-dependent epithelial proliferation and fluid secretion contribute to expansion. The initiating ciliary signal and an obligatory flow-calcium sequence remain unresolved. Cyst burden and interstitial injury can lead to hypertension and kidney failure. Less common causal genes produce distinct patterns of kidney size, fibrosis, age at onset and liver involvement; typical PKD1/PKD2 prognostic models do not automatically apply to them.

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Inheritance

Autosomal dominant inheritance HP:0000006

Autosomal dominant transmission with age- and genotype-dependent expression. Each child of a heterozygous affected individual has a 50% chance of inheriting the familial variant. De novo disease and mosaicism can explain an absent family history; they do not establish incomplete penetrance. Hypomorphic PKD1 alleles and some minor-gene forms can have reduced penetrance.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:40126492 SUPPORT REVIEW SYNTHESIS Other

"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.

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"Each child of an individual who is heterozygous for an ADPKD-causing pathogenic variant has a 50% chance of inheriting the pathogenic variant."

GeneReviews genetic counseling establishes transmission risk.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Family studies have identified nontruncating PKD1 variants that have reduced penetrance and are associated with much less severe disease"

GeneReviews distinguishes reduced penetrance of particular alleles from the dominant inheritance of the disorder.

◆

Subtypes

PKD1-related ADPKD (polycystic kidney disease 1) MONDO:0008263

PKD1 hgnc:9008 Autosomal dominant

The polycystin-1 form, and the majority of clinically ascertained ADPKD. In a cohort of 129 ADPKD patients who consecutively underwent genetic testing in a single centre in Italy, 86 carried a PKD1 variant against 28 in PKD2.

Show evidence (3 references)

PMID:38404363 SUPPORT Human Clinical

"Of the 129 enrolled patients, 86 (66.7%) had pathogenic variants in PKD1 and 28 (21.7%) in PKD2, loss of function pathogenic variants in the IFT140 gene were found in 3 unrelated patients (2.3%), no pathogenic variants were found in other ADPKD genes and 12 patients (9.3%) remained genetically..."

Sources the PKD1 and PKD2 counts quoted in this subtype description.

PMID:38404363 SUPPORT Human Clinical

"In this retrospective study, we tested the prevalence of the known causative genes of ADPKD-spectrum phenotype, including the PKD1, PKD2, GANAB, DNAJB11, ALG5, ALG and IFT140 genes, in a cohort of 129 ADPKD patients who consecutively underwent genetic testing in a single centre in Italy."

Sources the cohort described here, 129 consecutively tested patients at a single Italian centre.

CGGV:assertion_09d61dec-314b-4c5f-af2e-f22fc5992c12-2021-02-26T151356.823Z SUPPORT Other

ClinGen classifies the PKD1 relationship with ADPKD as Definitive.

PKD6 (DNAJB11-related, ADPKD/ADTKD hybrid) MONDO:0054842

DNAJB11 hgnc:14889 Autosomal dominant

Monoallelic DNAJB11 variants produce a phenotypic hybrid of ADPKD and autosomal dominant tubulointerstitial kidney disease: normal-sized cystic kidneys with progressive interstitial fibrosis and late-onset end-stage renal disease. DNAJB11 is a co-factor of the endoplasmic-reticulum chaperone BiP, and the lesion is a polycystin-1 maturation and trafficking defect rather than loss of the channel complex.

Show evidence (4 references)

PMID:29706351 SUPPORT Human Clinical

"DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD."

Defines the DNAJB11 clinical picture stated in this subtype description.

PMID:29706351 SUPPORT BACKGROUND Other

"DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins."

Sources the BiP co-factor role stated in this subtype description.

PMID:29706351 SUPPORT Human Clinical

"Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD."

Sources the polycystin-1 maturation and trafficking lesion stated in this subtype description.

+ 1 more reference

PKD7 (ALG5-related) MONDO:0031062

ALG5 hgnc:20266 Autosomal dominant

Monoallelic ALG5 variants produce an ADPKD-spectrum disorder of multiple small kidney cysts, progressive interstitial fibrosis and kidney function decline, with few or no liver cysts. ALG5 is an endoplasmic-reticulum enzyme that adds glucose to the assembling N-glycan precursor, and heterozygous loss is enough to impair polycystin-1 maturation.

Show evidence (5 references)

PMID:35896117 SUPPORT Human Clinical

"Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline."

Defines the ALG5 clinical picture stated in this subtype description.

PMID:35896117 SUPPORT Human Clinical

"Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age."

Sources the few-or-no-liver-cysts part of this subtype description.

PMID:35896117 SUPPORT BACKGROUND Other

"ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors."

Sources the enzymatic step stated in this subtype description.

+ 2 more references

PKD8 (NEK8-related) MONDO:0971178

NEK8 hgnc:13387 Autosomal dominant

Certain monoallelic NEK8 variants are recognized as an atypical ADPKD phenotype, ranging from childhood-onset kidney failure to typical ADPKD with few extrarenal anomalies. NEK8 is a ciliary kinase of the inversin compartment, so unlike the biogenesis genes the lesion is in the cilium itself. Biallelic NEK8 variants instead cause a syndromic renal ciliopathy, which is a different entity from this row.

Show evidence (4 references)

PMID:40677363 SUPPORT BACKGROUND Human Clinical

"Recently, certain monoallelic NEK8 variants have been recognized as atypical forms of ADPKD, with phenotypes from childhood-onset kidney failure to typical ADPKD with few extrarenal anomalies."

Sources the monoallelic NEK8 phenotype range stated in this subtype description; BACKGROUND because this letter restates the earlier cohort report.

PMID:40677363 SUPPORT BACKGROUND Human Clinical

"Biallelic pathogenic variants in NEK8 cause syndromic renal ciliopathies."

Sources the distinction drawn here between the monoallelic ADPKD phenotype and the biallelic syndromic ciliopathy.

PMID:40677363 SUPPORT BACKGROUND Other

"NEK8 localizes to the inversin compartment in cilia."

Sources the ciliary inversin-compartment localization stated in this subtype description.

+ 1 more reference

ALG9-associated ADPKD MONDO:0700000

ALG9 hgnc:15672 Autosomal dominant

ALG9 is an endoplasmic-reticulum enzyme that adds specific mannose residues to the assembling N-glycan precursor, and inactivating it impairs polycystin-1 maturation and glycosylation. Carriers identified from a population cohort rather than in a clinic nonetheless had kidney cysts, and in a multicentre screen of individuals with polycystic kidney or liver disease the ALG9 kidney phenotype was mild to moderate, with lower eGFR or kidney failure rare.

Show evidence (6 references)

CGGV:assertion_38d817af-0a28-4453-a00f-ffccadbd9936-2023-09-11T160000.000Z SUPPORT Other

ClinGen grades ALG9 Definitive against this row's own MONDO class, the only one of these rows scored at the child class rather than at the ADPKD parent.

PMID:31395617 SUPPORT In Vitro

"In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1."

The functional result behind the maturation defect stated in this subtype description.

PMID:31395617 SUPPORT BACKGROUND Other

"Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen."

Sources the enzymatic step stated in this subtype description.

+ 3 more references

◈

Mechanistic Hypotheses

Canonical PKD1/PKD2 / Primary Cilium / Cystogenesis Model

canonical_pkd1_pkd2_cilia_signaling_cystogenesis_model CANONICAL

Evidence balance 3 support 1 refute

Reduced polycystin dosage and dysregulated ciliary signaling provide the central model of typical PKD1/PKD2 ADPKD. Somatic PKD1/PKD2 changes in human cysts support a cellular second-hit component, while dosage thresholds and timing modify expression. Conditional mouse epistasis shows that intact cilia can promote cyst growth after polycystin loss. cAMP drives cyst epithelial proliferation and secretion and is therapeutically targeted by V2-receptor antagonism. An obligatory fluid-flow-to-ciliary-calcium sequence is not established.

The genuine falcon hypothesis exploration is consumed with primary-source qualifications: Kif3a/Ift20 epistasis, not Ift88 in the cited experiment; 57/63 epithelial samples and 14/24 whole cysts in distinct end-stage cohorts, not a universal second-hit frequency. Neither study phases every somatic hit or observes initiation directly. Calcium imaging challenges one proposed sensory mechanism, not the causal importance of PKD1/PKD2. Trial efficacy supports targeting the vasopressin-cAMP axis without proving the entire upstream model.

Deep research

Falcon citations 35 citations 2026-05-25T12:41:25.028800

Show evidence (4 references)

PMID:30042192 SUPPORT PRIMARY RESULT Human Clinical

"Pathogenic somatic mutations in PKD1/2 genes were identified in all patients and in 90% of cysts (57 out of 63; Supplemental Table 2, Table 2)."

Nine nephrectomy patients with end-stage disease; 57/63 sequenced cyst epithelia, not 57/63 patients or all cysts at initiation. Constitutional and somatic variants were not phased.

PMID:39702469 SUPPORT PRIMARY RESULT Human Clinical

"58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having at least one cyst with a somatic variant."

Six PKD1-positive patients with end-stage disease; smaller whole cysts, duplicate libraries and unique molecular identifiers. Sampling differs from epithelial enrichment. Structural variants, low-frequency loss of heterozygosity and variant phase were incompletely assessed.

PMID:23892607 SUPPORT PRIMARY RESULT Model Organism

"In the current study, we combined inactivation of Pkd1 and Pkd2 with loss of Kif3a and Ift20 to show that structurally intact cilia are required to promote rapid cyst growth following loss of PC1 or PC2."

Conditional mouse epistasis supports cyst-promoting signaling through retained cilia after polycystin loss. Effects depend on timing and model; Kif3a and Ift20 were the cilia genes tested.

+ 1 more reference

Discussions and Knowledge Gaps

Which cysts require somatic second hits, and when do those hits occur?

KNOWLEDGE GAP OPEN adpkd_second_hit_universality

Attached to

pathophysiology#Somatic PKD1 or PKD2 inactivation in cyst epithelium

Detection differed between epithelial-enriched samples and smaller whole cysts from end-stage kidneys. Variant phase, low-frequency structural variation and early disease remain incompletely assessed; neither a universal requirement nor its absence is established.

Show evidence (1 reference)

PMID:39702469 SUPPORT PRIMARY RESULT Human Clinical

"Another major limitation is interpreting data from end-stage kidney, in which it is not possible to determine whether a somatic variant was present at cyst initiation or is a result of secondary end-stage disease processes."

The primary paper states the temporal limitation directly.

Does correcting fatty acid oxidation improve human ADPKD independently of established cyst burden?

KNOWLEDGE GAP OPEN adpkd_metabolic_translation

Attached to

pathophysiology#Reduced epithelial fatty acid oxidation

The associated mouse dataset and paired cell assays implicate lipid metabolism but do not establish a human therapy. Sex, disease burden and model-specific absence of increased glycolysis limit generalization.

Show evidence (1 reference)

PMID:27077126 SUPPORT Other

"This study also suggests two important new lines for future investigation: how loss of Pkd1 results in a cell autonomous fatty acid oxidation defect and, more broadly, how altered cellular metabolism leads to dysregulation of tubular diameter and planar cell polarity."

Authors identify unresolved upstream and downstream links after the mouse and cell experiments.

⚙

Pathophysiology

Somatic PKD1 or PKD2 inactivation in cyst epithelium

Additional pathogenic somatic variants or loss of heterozygosity can further reduce polycystin dosage in focal cyst epithelium. Human evidence comes from end-stage nephrectomy cohorts and does not show that every cyst requires a detected second hit or establish its time of occurrence.

PKD1 hgnc:9008 PKD2 hgnc:9009

Downstream

Polycystin complex dosage loss at the renal primary cilium Additional somatic changes can reduce remaining functional polycystin dosage; allele phase is not resolved in the cited cohorts.

Show evidence (2 references)

PMID:30042192 SUPPORT PRIMARY RESULT Human Clinical

"Pathogenic somatic mutations in PKD1/2 genes were identified in all patients and in 90% of cysts (57 out of 63; Supplemental Table 2, Table 2)."

Nine nephrectomy patients with end-stage disease; 57/63 sequenced cyst epithelia, not 57/63 patients or all cysts at initiation. Constitutional and somatic variants were not phased.

PMID:39702469 SUPPORT PRIMARY RESULT Human Clinical

"58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having at least one cyst with a somatic variant."

Reduced GANAB glucosidase II activity

Loss of GANAB reduces the catalytic glucosidase II alpha subunit that trims N-linked glycans during ER protein quality control. The activity loss is inferred from loss of gene function; residual catalytic activity has not been quantified for every heterozygous ADPKD allele.

GANAB hgnc:4138

Glc2Man9GlcNAc2 oligosaccharide glucosidase activity GO:0106407 ↓ DECREASED

Downstream

Impaired polycystin maturation Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"GANAB encodes glucosidase II alpha, a protein that plays a role in trimming the glycans of glycosylated proteins"

GeneReviews identifies the enzyme and glycan-trimming function affected by GANAB loss.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Studies of PC1 have shown that its maturation and trafficking are particularly sensitive to loss of DNAJB11, glucosidase II alpha, alpha-1,2-mannosyltransferase, and dolichyl phosphate glucosyltransferase"

The review connects loss of the enzyme to PC1 maturation.

Reduced DNAJB11 co-chaperone function

DNAJB11 loss reduces the ER co-chaperone function involving binding immunoglobulin protein (BiP). The molecular-function binding identifies this interaction; it does not assert that each patient allele has been shown to lower intrinsic binding affinity.

DNAJB11 hgnc:14889

protein-folding chaperone binding GO:0051087 ↓ DECREASED

Downstream

Impaired polycystin maturation Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"It is a soluble ER protein that is a co-chaperone with binding immunoglobulin protein"

GeneReviews identifies DNAJB11 as a BiP co-chaperone; the following text describes efficient folding of membrane and secreted proteins.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Studies of PC1 have shown that its maturation and trafficking are particularly sensitive to loss of DNAJB11"

The review connects loss of DNAJB11 with PC1 maturation and trafficking.

Reduced ALG9 mannosyltransferase activity

Loss of ALG9 compromises its alpha-1,2-mannosyltransferase contribution to N-glycosylation and subsequent membrane-protein maturation. This is a different enzymatic step from the ALG5 and ALG8 glucosyltransferase reactions.

ALG9 hgnc:15672

ALG9 alpha-1,2-mannosyltransferase activity GO:0000030 ↓ DECREASED

Downstream

Impaired polycystin maturation Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"ALG9 is an alpha-1,2-mannosyltransferase and is involved in the glycosylation, folding, and trafficking of membrane and secreted proteins."

GeneReviews specifies ALG9 enzyme function and its role in membrane-protein maturation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

The review connects loss of ALG9 with PC1 maturation.

Reduced ALG5 dolichyl-phosphate glucosyltransferase activity

Reduction of ALG5 compromises dolichyl-phosphate glucosyltransferase activity in N-glycan biosynthesis, affecting PC1 maturation and localization. The gene-loss mechanism is distinguished from a direct catalytic assay of every heterozygous allele.

ALG5 hgnc:20266

dolichyl-phosphate beta-glucosyltransferase activity GO:0004581 ↓ DECREASED

Downstream

Impaired polycystin maturation Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"ALG5 is a dolichyl phosphate glucosyltransferase; reduction of ALG5 disrupts N-glycosylation and affects PC1 maturation and localization."

GeneReviews states both the enzyme function and the effect of ALG5 reduction on PC1.

Reduced ALG8 second-glucose transfer activity

ALG8 loss disrupts addition of the second glucose to the lipid-linked N-glycan precursor. Alg8-null renal epithelial cells have defective PC1 glycosylation and trafficking. Complete engineered loss supports the pathway but does not quantify activity loss in heterozygous human kidneys.

ALG8 hgnc:23161

dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity GO:0042283 ↓ DECREASED

Downstream

Impaired polycystin maturation Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.

Show evidence (2 references)

PMID:28375157 SUPPORT BACKGROUND Other

"where ALG8 (1) catalyzes the addition of the second glucose residue."

Figure 6 identifies the specific ALG8 enzymatic step in lipid-linked glycan synthesis.

PMID:28375157 SUPPORT PRIMARY RESULT In Vitro

"We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis."

The Alg8-null cell results support impaired PC1 biogenesis; they are not assays of heterozygous patient kidneys.

Reduced NEK8 p.Arg45Trp kinase activity

Immunoprecipitated p.Arg45Trp NEK8 expressed in 293T cells shows reduced autophosphorylation, supporting partial loss of kinase activity for this allele. This result is not generalized to p.Ile150Met or p.Lys157Gln and does not establish dominant-negative interference in heterozygous cells. The precise causal connection to altered ciliary PC2 trafficking remains unresolved.

NEK8 hgnc:13387

protein serine/threonine kinase activity GO:0004674 ↓ DECREASED

Show evidence (1 reference)

PMID:37598857 SUPPORT PRIMARY RESULT In Vitro

"the autophosphorylation level of NEK8-p.Arg45Trp was significantly lower than NEK8-WT, suggesting that p.Arg45Trp partially loses kinase activity."

The full-text result describes the 293T expression and immunoprecipitation assay; reduced autophosphorylation supports partial kinase impairment.

Proposed loss of IFT140-mediated TULP3 binding

Mechanism confidence: Provisional

IFT140 provides part of the TULP3-binding surface of IFT-A. Structural analysis and knockout-cell results motivate a hypothesis that IFT140 truncation disrupts TULP3-mediated cargo transport. Reduced binding in heterozygous ADPKD patient cells has not been demonstrated by these experiments, and IFT-A assembly does not require IFT140 in the reconstitution assay.

IFT140 hgnc:29077

IFT140 binding to TULP3 GO:0005515 ↓ DECREASED

Downstream

IFT140-associated ciliary dysfunction The proposed loss of the TULP3 interaction could compromise ciliary cargo transport; the monoallelic human mechanism remains provisional.

Show evidence (2 references)

PMID:36775821 SUPPORT PRIMARY RESULT In Vitro

"TULP3 interacts with the TPR-like domain of IFT140 and the TPR-like and zinc finger domains of IFT122 via its N-terminal region"

The human IFT-A structure directly identifies the IFT140-TULP3 interaction.

PMID:36775821 SUPPORT INDIRECT PRIMARY RESULT Other

"we hypothesize that one functional consequence of IFT140 truncation mutations is the disruption of TULP3-mediated cargo transport."

The source explicitly presents the truncation-to-transport mechanism as a hypothesis; the disease-specific binding defect remains provisional.

Impaired polycystin maturation

Disruption of endoplasmic-reticulum protein glycosylation or folding can reduce effective polycystin-1 maturation and trafficking. This is a shared mechanism for several minor-gene forms; individual proteins act at different maturation steps. ALG8 also belongs to this proteostasis group, although its clinical association is better established than the complete causal chain in patient kidneys.

Downstream

Polycystin complex dosage loss at the renal primary cilium Defective maturation reduces delivery of functional polycystin-1.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

GeneReviews synthesizes experimental evidence for DNAJB11, GANAB, ALG9 and ALG5 effects on PC1 maturation.

PMID:39899384 SUPPORT BACKGROUND Other

"Eight additional genes have been suggested to cause a monoallelic ADPKD-like phenotype; six of these encode endoplasmic reticulum–resident, proteostasis proteins: ALG5,18 ALG6,19 ALG8,20 ALG9,21 DNAJB11,22 and GANAB,23 plus the ciliogenesis genes, IFT140 and NEK8.24,25"

This is introductory mechanistic synthesis, not a new functional experiment in the ALG8/ALG9 clinical cohort.

Variant-dependent loss of ciliary polycystin-2 localization

NEK8 R45W and K157Q reduce ciliary PC2 localization when expressed in Nek8-null IMCD3 cells; I150M did not show this defect. This rescue assay does not itself establish dominant-negative interference in a heterozygous patient.

NEK8 hgnc:13387

Downstream

Polycystin complex dosage loss at the renal primary cilium Reduced PC2 localization can impair the ciliary complex; inference from variant-specific cell assays.

Show evidence (1 reference)

PMID:37598857 SUPPORT PRIMARY RESULT In Vitro

"However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia."

Mouse renal epithelial cell rescue experiments separate ciliary localization from total PC2 abundance and from clinical inheritance.

IFT140-associated ciliary dysfunction

Monoallelic pathogenic IFT140 variants affect a ciliary transport gene and produce a distinctive renal cystic phenotype. The precise steps from reduced IFT140 function to the adult cyst pattern are incompletely resolved; it is not equated with complete cilium deletion in epistasis models.

IFT140 hgnc:29077

Downstream

Renal cyst expansion Heterozygous IFT140 disease produces relatively few large renal cysts through incompletely resolved ciliary mechanisms.

Show evidence (2 references)

PMID:39899384 SUPPORT BACKGROUND Other

This is introductory mechanistic synthesis, not a new functional experiment in the ALG8/ALG9 clinical cohort.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Heterozygous pathogenic variants in IFT140 have been identified in 66 individuals from 38 families, with a mild PKD phenotype usually consisting of a few, larger cysts that can result in kidney enlargement and limited kidney insufficiency"

GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2 progression assumptions.

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 CL:0002518

PKD1 hgnc:9008 PKD2 hgnc:9009

primary cilium GO:0097731

Downstream

Cilium-dependent cyst-promoting signal disinhibition Loss of polycystins permits the cilia-dependent growth response demonstrated in conditional mice.

Increased renal epithelial cAMP signaling Polycystin dysfunction is associated with altered cAMP regulation; the intervening calcium events are context-dependent.

Reduced epithelial fatty acid oxidation Pkd1 deficiency reduces fatty acid oxidation in paired mouse renal epithelial cell lines; mediating steps remain unresolved.

Show evidence (4 references)

PMID:26877954 SUPPORT REVIEW SYNTHESIS Other

"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 REVIEW SYNTHESIS Other

"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.

PMID:30042192 SUPPORT PRIMARY RESULT Human Clinical

"Pathogenic somatic mutations in PKD1/2 genes were identified in all patients and in 90% of cysts (57 out of 63; Supplemental Table 2, Table 2)."

Nine nephrectomy patients with end-stage disease; 57/63 sequenced cyst epithelia, not 57/63 patients or all cysts at initiation. Constitutional and somatic variants were not phased.

+ 1 more reference

Cilium-dependent cyst-promoting signal disinhibition

With reduced polycystin function and retained cilia, a cyst-promoting signal is derepressed in conditional mouse models. Its molecular identity remains incompletely defined; the magnitude depends on developmental timing and the interval between polycystin loss and cilia involution.

kidney epithelial cell CL:0002518

primary cilium GO:0097731

Downstream

Renal epithelial proliferation Reduced proliferation accompanies suppression of cyst growth after cilia removal; the responsible signal is not uniformly explained by MAPK, cAMP or mTOR.

Show evidence (1 reference)

PMID:23892607 SUPPORT PRIMARY RESULT Model Organism

Conditional mouse epistasis supports cyst-promoting signaling through retained cilia after polycystin loss. Effects depend on timing and model; Kif3a and Ift20 were the cilia genes tested.

Altered cellular calcium signaling

Reduced cellular calcium signaling is one proposed contributor to cAMP dysregulation after polycystin dysfunction. The specific assertion that flow first evokes a ciliary calcium influx is contested and is not a required step in the represented causal chain.

kidney epithelial cell CL:0002518

Show evidence (2 references)

PMID:26877954 SUPPORT REVIEW SYNTHESIS Other

"Functional loss of PC1 at the cilium results in reduced cellular calcium signaling"

The review links polycystin loss at the cilium to reduced cellular calcium signaling.

PMID:27007841 REFUTE PRIMARY RESULT Model Organism

"Cilia-specific Ca(2+) influxes were not observed in physiological or even highly supraphysiological levels of fluid flow."

Ratiometric imaging in mouse-derived tissues and cells challenges obligatory flow-induced ciliary calcium influx. It does not exclude non-calcium mechanosensation or every role of cellular calcium.

Increased renal epithelial cAMP signaling

Elevated renal epithelial cAMP and PKA activity promote cyst expansion. Vasopressin V2-receptor signaling is a clinically actionable input; altered calcium-dependent adenylate cyclase and phosphodiesterase regulation is a proposed additional input rather than a universal initiating sequence.

kidney epithelial cell CL:0002518

Downstream

Renal epithelial proliferation cAMP/PKA can promote proliferative signaling in cystic epithelium.

Chloride-driven cyst fluid secretion cAMP/PKA promotes epithelial chloride transport and fluid secretion.

Show evidence (2 references)

PMID:26877954 SUPPORT REVIEW SYNTHESIS Other

"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.

PMID:26877954 SUPPORT REVIEW SYNTHESIS Other

"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"

This directly supports proliferation and chloride-driven secretion as cAMP/PKA-mediated cyst-growth features.

Renal epithelial proliferation

Increased proliferation of cyst-lining tubular epithelial cells enlarges the epithelial surface of developing cysts.

kidney epithelial cell CL:0002518

epithelial cell proliferation GO:0050673 ↑ INCREASED

Downstream

Renal cyst expansion Growth of the epithelial lining contributes to expanding cysts.

Show evidence (1 reference)

PMID:26877954 SUPPORT REVIEW SYNTHESIS Other

"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.

Chloride-driven cyst fluid secretion

Chloride transport by cyst-lining epithelium promotes fluid accumulation within the cyst lumen.

kidney epithelial cell CL:0002518

chloride transmembrane transport GO:1902476 ↑ INCREASED

Downstream

Renal cyst expansion Transepithelial fluid secretion increases cyst volume.

Show evidence (1 reference)

PMID:26877954 SUPPORT REVIEW SYNTHESIS Other

This directly supports proliferation and chloride-driven secretion as cAMP/PKA-mediated cyst-growth features.

Renal cyst expansion

Progressive epithelial cyst enlargement increases total kidney volume and distorts surrounding tubules and vessels in typical ADPKD. Minor-gene forms can show small cysts or fibrosis without marked enlargement.

kidney epithelial cell CL:0002518

Downstream

Renal parenchymal injury and fibrosis Enlarging cysts destroy normal renal parenchyma and reduce kidney function over time.

Renal cysts

Hematuria

Flank pain

Recurrent urinary tract infections

Enlarged kidney

Uric acid nephrolithiasis

Calcium oxalate nephrolithiasis

Pyelonephritis

Renal vascular resistance increase Cyst-associated vascular distortion contributes to abnormal renal hemodynamics.

Impaired renal concentrating ability Tubular dysfunction produces an early concentrating defect, which may precede reduced GFR.

Show evidence (1 reference)

PMID:40126492 SUPPORT REVIEW SYNTHESIS Other

"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.

Renal parenchymal injury and fibrosis

Cyst-associated tissue remodeling, extracellular-matrix accumulation and fibrosis reduce functioning renal parenchyma. This tissue injury underlies declining filtration and eventual kidney failure in progressive disease.

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.

Renal insufficiency

Decreased glomerular filtration rate

Elevated circulating creatinine concentration

Albuminuria

Abnormal urinary electrolyte concentration

Show evidence (1 reference)

PMID:26877954 SUPPORT REVIEW SYNTHESIS Other

"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.

Renal vascular resistance increase

Abnormal renal hemodynamics and renin-angiotensin activity contribute to early hypertension, often before GFR declines.

Downstream

Hypertension Increased renal vascular resistance and altered sodium handling contribute to elevated blood pressure.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Hypertension often develops in young adults, and even in childhood, and usually before any decline in GFR."

GeneReviews places hypertension before filtration loss and describes increased vascular resistance and normal or high renin activity.

Reduced epithelial fatty acid oxidation

Pkd1-deficient mouse renal epithelial cell lines show reduced fatty acid oxidation. The same study did not find increased glycolysis, and human therapeutic relevance remains unproven.

Show evidence (2 references)

PMID:27077126 SUPPORT PRIMARY RESULT In Vitro

"We found that renal epithelial cells lacking Pkd1 have cell autonomous defects in fatty acid oxidation."

Paired immortalized mouse renal epithelial cell lines; the bulk kidney metabolomic signature is a separate model-organism observation.

PMID:27077126 SUPPORT PRIMARY RESULT In Vitro

"Changes in glycolysis were not observed (Fig. 3, c and d, and Supplementary Figure S5)."

This experiment does not support a universal switch to increased glycolysis.

Hepatic epithelial cyst expansion

Polycystin dysfunction also affects hepatic cyst epithelium. Cyst growth can produce an extensive liver burden, but symptomatic hepatomegaly is much less common than imaging-detected liver cysts.

cholangiocyte CL:1000488

PKD1 hgnc:9008 PKD2 hgnc:9009

Downstream

Hepatic cysts Hepatic cyst expansion produces imaging-detectable cysts.

Polycystic liver disease Extensive hepatic cyst burden produces PLD.

Show evidence (1 reference)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD), most often in females."

GeneReviews distinguishes age-dependent liver cysts from severe symptomatic PLD.

Vascular polycystin dysfunction

Reduced polycystin function at vascular sites is implicated in arterial complications. The tissue mechanisms are less resolved than the renal epithelial pathway and are not effects of renal-cell cilia on every extrarenal organ.

PKD1 hgnc:9008 PKD2 hgnc:9009

Downstream

Cerebral arterial dilatation Vascular polycystin dysfunction is implicated in cerebral arterial abnormalities.

Aortic root aneurysm An incompletely defined arterial-wall process contributes to aortic complications.

Abnormal systemic arterial morphology Broader arterial changes are reported; intermediates remain unspecified.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"The localization of polycystins to other phenotypic sites (e.g., the vascular system) indicates that reductions in the level of these proteins underlie disease complications such as intracranial aneurysms"

GeneReviews provides the vascular-site hypothesis; molecular intermediates remain incompletely defined.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 5

Hypertension FREQUENT HP:0000822

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (3 references)

ORPHA:730 SUPPORT Other

"HP:0000822 | Hypertension | Frequent (79-30%)"

Orphanet lists hypertension as frequent.

PMID:40126492 SUPPORT REVIEW SYNTHESIS Other

"Hypertension affects 70% to 80% of patients with ADPKD"

The 2025 review quantitatively supports hypertension as a common feature.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Hypertension often develops in young adults, and even in childhood, and usually before any decline in GFR."

GeneReviews supports early onset, which is not captured by a cross-sectional catalog frequency.

Mitral valve prolapse OCCASIONAL HP:0001634

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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 HP:0002616

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0002616 | Aortic root aneurysm | Occasional (29-5%)"

Orphanet lists aortic root aneurysm as occasional.

Cerebral arterial dilatation OCCASIONAL Dilatation of the cerebral artery HP:0004944

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype. The source names intracranial aneurysms without specifying every aneurysm morphology; the broader arterial-dilatation binding is retained rather than assuming every lesion is a berry aneurysm.

Show evidence (3 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 REVIEW SYNTHESIS Other

"approximately 9% to 14% develop intracranial aneurysms"

The review quantifies intracranial aneurysm risk in ADPKD.

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"Overall, the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage."

GeneReviews documents the vascular risk and its familial enrichment.

Abnormal systemic arterial morphology OCCASIONAL HP:0011004

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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.

Digestive 4

Hepatic cysts VERY_FREQUENT HP:0001407

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (3 references)

ORPHA:730 SUPPORT Other

"HP:0001407 | Hepatic cysts | Very frequent (99-80%)"

Orphanet lists hepatic cysts as very frequent.

PMID:40126492 SUPPORT REVIEW SYNTHESIS Other

"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.

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD), most often in females."

GeneReviews distinguishes age-dependent liver cysts from severe symptomatic PLD.

Polycystic liver disease OCCASIONAL HP:0006557

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0006557 | Polycystic liver disease | Occasional (29-5%)"

Orphanet lists polycystic liver disease as occasional.

Pancreatic cysts OCCASIONAL HP:0001737

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0001737 | Pancreatic cysts | Occasional (29-5%)"

Orphanet lists pancreatic cysts as occasional.

Hernia of the abdominal wall HP:0004299

Show evidence (1 reference)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias."

GeneReviews clinical characteristics include abdominal wall hernias.

Endocrine 1

Pituitary growth hormone cell adenoma VERY_RARE HP:0011760

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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.

Genitourinary 16

Renal cysts VERY_FREQUENT HP:0000107

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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 HP:0000083

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0000083 | Renal insufficiency | Very frequent (99-80%)"

Orphanet lists renal insufficiency as very frequent.

Decreased glomerular filtration rate VERY_FREQUENT HP:0012213

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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.

Hematuria FREQUENT HP:0000790

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0000790 | Hematuria | Frequent (79-30%)"

Orphanet lists hematuria as frequent.

Chronic kidney disease FREQUENT HP:0012622

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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 HP:0003774

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (3 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 REVIEW SYNTHESIS Other

"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.

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"Approximately 50% of individuals with ADPKD have end-stage kidney disease (ESKD) by age 60 years."

Historical aggregate natural history summarized by GeneReviews; gene and variant class strongly modify prognosis.

Albuminuria FREQUENT HP:0012592

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0012592 | Albuminuria | Frequent (79-30%)"

Orphanet lists albuminuria as frequent.

Abnormal urinary electrolyte concentration FREQUENT HP:0012591

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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 HP:0000010

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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.

Enlarged kidney OCCASIONAL HP:0000105

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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 HP:0000791

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0000791 | Uric acid nephrolithiasis | Occasional (29-5%)"

Orphanet lists uric acid nephrolithiasis as occasional.

Calcium oxalate nephrolithiasis OCCASIONAL HP:0008672

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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 HP:0012330

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0012330 | Pyelonephritis | Occasional (29-5%)"

Orphanet lists pyelonephritis as occasional.

Reduced sperm motility OCCASIONAL HP:0012207

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0012207 | Reduced sperm motility | Occasional (29-5%)"

Orphanet lists reduced sperm motility as occasional.

Impaired renal concentrating ability HP:0004727

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Reduction in urinary concentrating capacity and excretion of ammonia occur early in individuals with ADPKD."

GeneReviews describes early functional tubular abnormalities.

Seminal vesicle cysts HP:6000191

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Seminal vesicle cysts, present in 40% of males, rarely result in infertility."

GeneReviews provides a male-specific estimate; KDIGO 2025 cautions against inferring excess infertility.

Metabolism 1

Elevated circulating creatinine concentration VERY_FREQUENT HP:0003259

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

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.

Nervous System 1

Arachnoid cyst OCCASIONAL HP:0100702

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0100702 | Arachnoid cyst | Occasional (29-5%)"

Orphanet lists arachnoid cyst as occasional.

Respiratory 1

Bronchiectasis HP:0002110

Show evidence (1 reference)

url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf SUPPORT REVIEW SYNTHESIS Other

"Bronchiectasis 19 –37 Incidental radiologic ﬁnding, typically of no clinical signi ﬁcance"

Guideline table 4 reports an imaging association rather than symptomatic respiratory disease.

Constitutional 1

Flank pain FREQUENT HP:0030157

Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.

Show evidence (1 reference)

ORPHA:730 SUPPORT Other

"HP:0030157 | Flank pain | Frequent (79-30%)"

Orphanet lists flank pain as frequent.

🧬

Genetic Associations

PKD1 pathogenic variants (CAUSATIVE)

Gene: PKD1 hgnc:9008 gene page

Show evidence (6 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 REVIEW SYNTHESIS Other

"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

ClinGen classifies the PKD1-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.

+ 3 more references

PKD2 pathogenic variants (CAUSATIVE)

Gene: PKD2 hgnc:9009 gene page

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 REVIEW SYNTHESIS Other

"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

ClinGen classifies the PKD2-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.

GANAB pathogenic variants (CAUSATIVE)

Gene: GANAB hgnc:4138 gene page

Show evidence (2 references)

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.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Pathogenic variants cause mild cystic kidney disease, usually without a decline in kidney function, with the majority of affected individuals having liver cysts"

GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2 progression assumptions.

DNAJB11 pathogenic loss-of-function variants (CAUSATIVE)

Gene: DNAJB11 hgnc:14889 gene page

Show evidence (3 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

ClinGen classifies the DNAJB11-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"The phenotype is quite consistent and results in the development of small, bilateral kidney cysts, usually without kidney enlargement"

GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2 progression assumptions.

IFT140 pathogenic loss-of-function variants (CAUSATIVE)

Gene: IFT140 hgnc:29077 gene page

Show evidence (3 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

ClinGen classifies the IFT140-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2 progression assumptions.

ALG5 pathogenic variants (CAUSATIVE)

Gene: ALG5 hgnc:20266 gene page

Show evidence (3 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

ClinGen classifies the ALG5-autosomal dominant polycystic kidney disease gene-disease relationship as moderate with autosomal dominant inheritance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"The typical phenotype is non-enlarged cystic kidneys and interstitial fibrosis with few liver cysts leading to ESKD in older individuals."

GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2 progression assumptions.

ALG9 pathogenic loss-of-function variants (CAUSATIVE)

Gene: ALG9 hgnc:15672 gene page

Show evidence (2 references)

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.

PMID:39899384 SUPPORT PRIMARY RESULT Human Clinical

"ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR."

Primary clinical and genotype-first cohorts support the gene-disease relationship while showing limited penetrance for clinically important kidney dysfunction. The clinical cohort included 51 ALG8 and 23 ALG9 families among 3935 referrals.

NEK8 kinase-domain missense variants (CAUSATIVE)

Gene: NEK8 hgnc:13387 gene page

Show evidence (3 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

ClinGen classifies the NEK8-autosomal dominant polycystic kidney disease gene-disease relationship as strong with autosomal dominant inheritance.

PMID:37598857 SUPPORT PRIMARY RESULT Human Clinical

"Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations."

Twelve families with specific kinase-domain missense variants; not evidence that all heterozygous NEK8 loss-of-function alleles cause this phenotype.

ALG8 pathogenic variants (CAUSATIVE)

Gene: ALG8 hgnc:23161 gene page

Show evidence (2 references)

CGGV:assertion_13259bf6-e954-4159-b247-c9685638e537-2025-03-10T160000.000Z SUPPORT Other

ClinGen classifies the ALG8-autosomal dominant polycystic kidney disease gene-disease relationship as definitive with autosomal dominant inheritance.

PMID:39899384 SUPPORT PRIMARY RESULT Human Clinical

"ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR."

💊

Medical Actions

Tolvaptan vasopressin V2 receptor antagonist therapy

Action: Pharmacotherapy NCIT:C15986

Agent: tolvaptan CHEBI:32246

Platform: Small molecule

Tolvaptan slows kidney-volume growth and eGFR decline in selected adults with rapidly progressive ADPKD. KDIGO 2025 recommends initiation with eGFR at least 25 mL/min/1.73 m2 and documented rapid-progression risk; decisions above age 55 are individualized. Aquaresis requires reliable water access and interruption during volume depletion. Liver toxicity requires baseline and regular monitoring under local prescribing requirements. Trial eGFR benefits are not direct observations of a delay in dialysis.

Mechanism Target:

INHIBITS Increased renal epithelial cAMP signaling — Vasopressin V2 receptor antagonism lowers the cAMP drive that supports cyst epithelial proliferation and secretion.

Show evidence (2 references)

PMID:26877954 SUPPORT REVIEW SYNTHESIS Other

Mechanistic review supports the targeted cAMP pathway; randomized outcomes establish efficacy separately.

PMID:23121377 SUPPORT BACKGROUND Model Organism

"Studies of animal models implicate the antidiuretic hormone arginine vasopressin and its second messenger adenosine-3′,5′-cyclic monophosphate (cAMP) as promoters of kidney-cyst cell proliferation and luminal fluid secretion."

The TEMPO trial introduction summarizes the preclinical vasopressin-cAMP rationale; it is not a human mechanistic measurement.

Target Phenotypes: Renal cyst HP:0000107 Decreased glomerular filtration rate HP:0012213

Show evidence (5 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"

TEMPO 3:4 randomized 1445 adults aged 18–50 with total kidney volume at least 750 mL and preserved creatinine clearance. TKV increased 2.8% versus 5.5% yearly; discontinuation was 23% versus 14%. The full text reports aquaretic adverse effects and liver enzyme elevations.

PMID:40126492 SUPPORT REVIEW SYNTHESIS Other

"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.

PMID:29105594 SUPPORT PRIMARY RESULT Human Clinical

"The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group"

REPRISE primary endpoint over one year after a tolerability run-in; 1370 randomized, with 1331 contributing to the primary analysis. The run-in selected patients able to tolerate treatment.

+ 2 more references

ACE inhibitor or angiotensin receptor blocker therapy

Action: ACE inhibitor or angiotensin receptor blocker therapy Ontology label: Antihypertensive Therapy NCIT:C172184

Agent: ACE Inhibitor NCIT:C247 Angiotensin II Receptor Antagonist NCIT:C66930

Platform: Small molecule

Use an ACE inhibitor or an ARB as first-line blood-pressure therapy; avoid routine dual blockade. KDIGO targets differ by age, CKD stage and measurement method: in hypertensive adults aged 18–49 with G1–G2, home BP at or below 110/75 mm Hg if tolerated; at age 50 or above and/or G3–G5, standardized office systolic BP below 120 if tolerated. HALT-PKD reduced kidney-volume growth with intensive control but did not show an overall eGFR benefit.

Target Phenotypes: Hypertension HP:0000822

Show evidence (6 references)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"Treatment for hypertension may include ACE inhibitors or angiotensin II receptor blockers and diet modification."

GeneReviews supports renin-angiotensin blockade.

PMID:25399733 SUPPORT PRIMARY RESULT Human Clinical

"The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006)"

HALT-PKD enrolled younger hypertensive participants with preserved eGFR; the volume endpoint does not establish an overall eGFR benefit or a benefit from dual blockade.

url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf SUPPORT REVIEW SYNTHESIS Other

"For those aged $50 years and/or with CKD G3 –G5, we recommend a target mean systolic blood pressure of <120 mm Hg, if tolerated, assessed using standardized of ﬁce BP measurement."

PDF extraction renders the at-least sign as a dollar sign; the clinical target refers to age 50 or above and/or CKD G3–G5, using standardized office measurement.

+ 3 more references

Dietary sodium restriction

Action: dietary sodium intake avoidance Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Moderate sodium restriction, generally below 2000 mg/day, is part of blood-pressure and CKD management. It is not interchangeable with pharmacologic blood-pressure control or established as a stand-alone cure for cystogenesis.

Target Phenotypes: Hypertension HP:0000822 Chronic kidney disease HP:0012622

Show evidence (1 reference)

PMID:40126492 SUPPORT REVIEW SYNTHESIS Other

"dietary sodium restriction (<2000 mg/d)"

This directly supports sodium restriction as a treatment component.

Genetic counseling

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counsel about variable expression, a 50% transmission risk for a heterozygous familial variant, cascade testing of adults, and prenatal or preimplantation testing when the familial variant is known. Childhood testing is a shared decision with the family and appropriate specialists; absence of symptoms does not establish absence of disease.

Show evidence (2 references)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"Once the ADPKD-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews genetic counseling supports reproductive testing options.

url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf SUPPORT REVIEW SYNTHESIS Other

"Expert counseling about diagnostic options, delivered by a team that includes a pediatric nephrologist and a geneticist, should be offered."

KDIGO recommends shared decisions about diagnosis in at-risk children, updating older categorical approaches.

Individualized kidney pain management

Action: Individualized kidney pain management Ontology label: Supportive Care NCIT:C15747

Investigate acute pain for hemorrhage, stones or infection. Persistent pain is managed stepwise with noninvasive measures and individualized analgesia; selected refractory cases require specialist cyst-directed procedures or nerve interventions. Long-term nephrotoxic analgesic exposure should be avoided.

Target Phenotypes: Flank pain HP:0030157

Show evidence (1 reference)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"Conservative treatment of flank pain includes nonopioid agents, tricyclic antidepressants, narcotic analgesics, and splanchnic nerve blockade."

GeneReviews supplies management options; choice requires renal-function and adverse-effect assessment.

Treatment of kidney cyst infection

Action: Treatment of kidney cyst infection Ontology label: Antibiotic Therapy NCIT:C15620

Platform: Small molecule

Culture-guided antibiotics with adequate cyst penetration are required for suspected or confirmed kidney cyst infection, typically for 4–6 weeks under KDIGO guidance. This duration should not be transferred to uncomplicated lower urinary infection. Drug selection must consider susceptibility, renal function and adverse effects.

Show evidence (1 reference)

url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf SUPPORT REVIEW SYNTHESIS Other

"A lipid-soluble antibiotic (e.g., trimethoprim- sulfamethoxazole, ﬂuoroquinolone) may have better pene- tration into the cysts, and should be used if possible."

KDIGO kidney-cyst infection guidance; adjacent full text specifies 4–6 weeks and cautions about fluoroquinolone adverse effects.

Dialysis for kidney failure

Action: Dialysis for kidney failure Ontology label: Dialysis NCIT:C15221

Provide kidney replacement therapy when clinically indicated; modality is individualized according to residual function, organ enlargement and patient preference.

Target Phenotypes: Stage 5 chronic kidney disease HP:0003774

Show evidence (1 reference)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"ESKD is treated with dialysis and transplantation."

GeneReviews management of kidney failure.

Kidney transplantation

Action: Kidney transplantation Ontology label: Kidney Transplantation NCIT:C15265

Platform: Surgery

Transplantation is the preferred replacement option for suitable candidates, with preemptive transplantation when feasible. Related donors require careful exclusion of familial disease; native nephrectomy is reserved for selected indications.

Target Phenotypes: Stage 5 chronic kidney disease HP:0003774

Show evidence (1 reference)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"ESKD is treated with dialysis and transplantation."

GeneReviews management of kidney failure.

Somatostatin analogue therapy for symptomatic polycystic liver disease

Action: Somatostatin analogue therapy for symptomatic polycystic liver disease Ontology label: Somatostatin Analog Therapy NCIT:C15449

Long-acting somatostatin analogues may be used for marked cystic hepatomegaly with severe volume-related symptoms in expert care. Assess benefit after 6–12 months and discontinue without benefit. This is a liver-volume/symptom indication, not proof of preserved kidney function or a recommendation for every asymptomatic liver cyst.

Target Phenotypes: Polycystic liver disease HP:0006557

Show evidence (1 reference)

url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf SUPPORT REVIEW SYNTHESIS Other

"We recommend prescribing long-acting somatostatin analogues in people with marked cystic hepatomegaly in PLD with severe volume-related symptoms."

KDIGO 2025 integrates four randomized trials showing reduced liver-volume growth; evaluate symptoms and volume response.

Specialist intervention for severe polycystic liver disease

Action: Specialist intervention for severe polycystic liver disease Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Selected symptomatic patients may require aspiration/sclerotherapy, fenestration, resection or transplantation according to cyst distribution, liver volume and local expertise. These procedures are not indicated solely because liver cysts are visible.

Target Phenotypes: Polycystic liver disease HP:0006557

Show evidence (1 reference)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"Severe symptoms may require percutaneous aspiration and sclerosis, laparoscopic fenestration, combined hepatic resection and cyst fenestration, liver transplantation, or selective hepatic artery embolization."

GeneReviews describes options for severe liver symptoms; KDIGO 2025 emphasizes expert centers and individualized selection.

Avoidance of nephrotoxic and liver-cyst-promoting exposures

Action: ADPKD risk-reduction counseling Ontology label: Counseling NCIT:C61547

Avoid long-term nephrotoxic analgesic use, smoking and high-salt intake. In substantial PLD, discuss estrogen exposure and contraceptive or hormone-treatment alternatives with clinicians because estrogen can promote liver cyst growth.

Show evidence (1 reference)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"Long-term administration of nephrotoxic agents, high levels of caffeine, high-salt diet, smoking, and obesity, and in individuals with severe PLD, use of estrogens and possibly progestogens."

GeneReviews agents/circumstances to avoid; estrogen counseling is reinforced by KDIGO 2025.

🔬

Biochemical Markers

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.

🔬

Diagnosis

Age- and family-history-specific kidney imaging

In individuals with an affected first-degree relative and typical PKD1/PKD2 risk, ultrasound criteria include at least three total renal cysts at age 15–39, at least two in each kidney at 40–59, and at least four in each kidney at age 60 or above. MRI can resolve equivocal cases. A negative scan in a younger relative does not exclude all genotypes; criteria for incidental cysts without family history and for minor genes require separate assessment.

Age- and family-history-specific kidney imaging NCIT:C17230

Show evidence (2 references)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"The diagnosis of ADPKD is established in a proband with age-specific kidney imaging criteria and either an affected first-degree relative with ADPKD or a heterozygous pathogenic variant in PKD1, PKD2, or one of the less common associated genes (ALG5, ALG9, DNAJB11, GANAB, IFT140) identified by..."

GeneReviews establishes imaging plus family/genetic context.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"The presence of three or more (unilateral or bilateral) kidney cysts in an individual age 15-39 years"

GeneReviews gives age-specific ultrasound criteria in a relative at 50% risk.

Molecular confirmation and familial testing

Use a cystic-kidney multigene assay appropriate to the phenotype. PKD1 pseudogene homology, copy-number variation and low-level mosaicism need assay-specific coverage; a negative routine panel or a variant of uncertain significance does not establish or exclude every form. Test a known familial pathogenic variant when evaluating relatives or related donors.

Molecular confirmation and familial testing NCIT:C15709

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Multigene panels using next-generation sequencing should be carefully designed to maximize identification of a PKD1 pathogenic variant, which is complicated by several highly homologous pseudogenes"

GeneReviews explains a major assay-design limitation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Specific analysis is required to detect exon or whole-gene deletions/duplications."

Sequence-only testing does not capture every relevant variant class.

MRI total kidney volume risk stratification

Mayo Imaging Classification uses age and height-adjusted total kidney volume to predict progression in typical class-1 PKD1/PKD2 ADPKD. It does not establish the diagnosis and is not validated for atypical class-2 morphology or minor-gene forms. Prognosis incorporates eGFR trajectory and genotype where available.

magnetic resonance imaging procedure NCIT:C16809

Show evidence (2 references)

PMID:40126492 SUPPORT REVIEW SYNTHESIS Other

"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"

This supports total kidney volume imaging for ADPKD risk stratification.

url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf SUPPORT REVIEW SYNTHESIS Other

"Prognostic information is valid for only class 1 patients with typical imaging ﬁndings"

KDIGO limits MIC prognostic interpretation to typical morphology.

Risk-based intracranial aneurysm screening

Discuss screening in people with personal subarachnoid hemorrhage or family intracranial aneurysm, subarachnoid hemorrhage or unexplained sudden death who could benefit from treatment. Other situations, uncertain family history and patient preferences require shared decisions. Noncontrast time-of-flight MRA is preferred; negative high-risk screening may be repeated after an individualized 5–10-year interval.

Risk-based intracranial aneurysm screening NCIT:C16809

Show evidence (2 references)

PMID:20301424 SUPPORT REVIEW SYNTHESIS Other

"MRA examination for intracranial aneurysms in adults determined to be at high risk."

GeneReviews supports targeted surveillance; KDIGO 2025 provides current risk and modality details.

url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf SUPPORT REVIEW SYNTHESIS Other

"We recommend screening for ICA in people with ADPKD and a personal history of SAH or a positive family history of ICA, SAH, or unexplained sudden death if the person will be eligible for treatment and has a reasonable life expectancy."

Current guideline defines the high-risk screening population; other preferences and uncertain family history require discussion.

Blood pressure surveillance

Follow blood pressure throughout the disease course. KDIGO 2025 recommends annual standardized office assessment from age five in children and adolescents with or at risk for ADPKD, with ambulatory monitoring for selected higher-risk children. This updates the longer interval in the 2022 GeneReviews summary.

Blood pressure surveillance NCIT:C167233

Show evidence (1 reference)

url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf SUPPORT REVIEW SYNTHESIS Other

"BP control in children and adolescents with ADPKD. Standar- dized ofﬁce BP measurement should be performed annually in"

Annual standardized office BP recommendation; the sentence continues after figure 9 with children aged at least five years and adolescents with or at risk for ADPKD.

📊

Prevalence

United States

Point Prevalence 93.0 per 100,000 1–9 per 10,000

Show evidence (1 reference)

PMID:40126492 SUPPORT REVIEW SYNTHESIS Other

"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."

The 2025 clinical review provides a current US prevalence estimate and quantifies the contribution to kidney failure.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Polycystic Kidney Disease:

Autosomal recessive polycystic kidney disease

Overlapping Features PKHD1-related recessive disease commonly presents neonatally with enlarged cystic kidneys and congenital hepatic fibrosis; severe early ADPKD remains a differential, so onset alone is insufficient.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Pulmonary hypoplasia, early-onset kidney failure, liver fibrosis rather than cysts, TKV ↓ over time (rather than ↑)"

GeneReviews differential table contrasts PKHD1-related ARPKD with typical ADPKD.

Autosomal dominant tubulointerstitial kidney disease

Overlapping Features UMOD, MUC1 and related disorders can include renal cysts, but interstitial fibrosis and declining function without marked kidney enlargement predominate. Early gout suggests UMOD/REN disease. DNAJB11 and ALG5 phenotypes overlap this distinction.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Fibrosis rather than cysts is the major kidney phenotype."

GeneReviews differential table states this discriminator for MUC1/UMOD-related disease.

Tuberous sclerosis complex and PKD1-TSC2 contiguous deletion

Overlapping Features Angiomyolipomas, characteristic skin/brain lesions or cardiac rhabdomyomas suggest tuberous sclerosis. A contiguous deletion involving PKD1 and TSC2 can combine severe early cystic disease with tuberous sclerosis features.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf SUPPORT REVIEW SYNTHESIS Other

"Kidney angiomyolipomas, skin & brain manifestations, rhabdomyomas, lymphangioleiomyomatosis"

GeneReviews differential table lists tuberous sclerosis features and points to the PKD1-TSC2 contiguous-deletion context.

📊

Related Datasets

Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease metabolomics_workbench:ST000878

mouse METABOLOMICS

Mouse kidney metabolomics associated with PMID:27077126. The primary study analyzed 14 male kidneys, including eight Pkd1 mutants; bulk metabolite changes often tracked kidney disease burden. Its separate paired cell-line experiments found impaired fatty acid oxidation without increased glycolysis. This is a mouse tissue dataset, not a patient cohort or evidence of a clinically effective diet. The accession was independently resolved against Metabolomics Workbench during this review.

🔬

Clinical Trials

NCT00428948 PHASE_III COMPLETED

TEMPO 3:4 randomized 1445 adults aged 18–50 with enlarged kidneys and preserved creatinine clearance for three years. Primary kidney-volume growth was slower with tolvaptan, with more aquaretic and hepatic adverse events and discontinuations; trial selection limits generalization.

Target Phenotypes: Renal cyst HP:0000107 Decreased glomerular filtration rate HP:0012213

Show evidence (2 references)

clinicaltrials:NCT00428948 SUPPORT Other

"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.

NCT02160145 PHASE_III COMPLETED

REPRISE randomized 1370 adults after placebo and tolvaptan run-in to one year of tolvaptan or placebo in later-stage disease. Entry eGFR and age restrictions and exclusion of run-in intolerance limit generalizability. The primary eGFR difference was 1.27 mL/min/1.73 m2; dialysis delay was not an observed endpoint.

Target Phenotypes: Decreased glomerular filtration rate HP:0012213

Show evidence (3 references)

clinicaltrials:NCT02160145 SUPPORT Other

"The purpose of the study is to determine whether tolvaptan is effective and safe for the treatment of late-stage chronic kidney disease due to autosomal dominant polycystic kidney disease (ADPKD)"

Registry description establishes trial purpose.

PMID:29105594 SUPPORT PRIMARY RESULT Human Clinical

REPRISE primary endpoint over one year after a tolerability run-in; 1370 randomized, with 1331 contributing to the primary analysis. The run-in selected patients able to tolerate treatment.

url:https://discovery.ucl.ac.uk/10050941/1/nejmoa1710030.pdf SUPPORT PRIMARY RESULT Human Clinical

"1496 patients entered the single-blind tolvaptan period, of whom 126 withdrew before randomization"

Full-text REPRISE results document run-in attrition before randomized follow-up; tolerability among randomized participants therefore does not describe every screened or run-in participant.

{ }

Source YAML

click to show

name: Autosomal Dominant Polycystic Kidney Disease
creation_date: '2026-05-08T16:23:43Z'
category: Mendelian
description: >-
  Autosomal dominant polycystic kidney disease (ADPKD) is an inherited multisystem disorder,
  most often caused by PKD1 or PKD2 variants, with progressive renal epithelial cysts, frequent
  liver cysts and vascular complications. Reduced polycystin function permits cyst-promoting
  ciliary signaling; cAMP-dependent epithelial proliferation and fluid secretion contribute
  to expansion. The initiating ciliary signal and an obligatory flow-calcium sequence remain
  unresolved. Cyst burden and interstitial injury can lead to hypertension and kidney failure.
  Less common causal genes produce distinct patterns of kidney size, fibrosis, age at onset
  and liver involvement; typical PKD1/PKD2 prognostic models do not automatically apply to them.
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
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 93.0
  percentage: 0.093%
  evidence:
  - reference: PMID:40126492
    reference_title: 'Autosomal Dominant Polycystic Kidney Disease: A Review.'
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant transmission with age- and genotype-dependent expression. Each child
    of a heterozygous affected individual has a 50% chance of inheriting the familial variant.
    De novo disease and mosaicism can explain an absent family history; they do not establish
    incomplete penetrance. Hypomorphic PKD1 alleles and some minor-gene forms can have reduced
    penetrance.
  evidence:
  - reference: PMID:40126492
    reference_title: 'Autosomal Dominant Polycystic Kidney Disease: A Review.'
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Each child of an individual who is heterozygous for an ADPKD-causing pathogenic variant
      has a 50% chance of inheriting the pathogenic variant.
    explanation: GeneReviews genetic counseling establishes transmission risk.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Family studies have identified nontruncating PKD1 variants that have reduced penetrance
      and are associated with much less severe disease
    explanation: GeneReviews distinguishes reduced penetrance of particular alleles from the dominant inheritance of the disorder.
has_subtypes:
- name: PKD1
  display_name: PKD1-related ADPKD (polycystic kidney disease 1)
  subtype_term:
    preferred_term: polycystic kidney disease 1
    term:
      id: MONDO:0008263
      label: polycystic kidney disease 1
  genes:
  - preferred_term: PKD1
    term:
      id: hgnc:9008
      label: PKD1
  description: >-
    The polycystin-1 form, and the majority of clinically ascertained ADPKD. In
    a cohort of 129 ADPKD patients who consecutively underwent genetic testing in
    a single centre in Italy, 86 carried a PKD1 variant against 28 in PKD2.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:38404363
    reference_title: "Monoallelic pathogenic IFT140 variants are a common cause of autosomal dominant polycystic kidney disease-spectrum phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 129 enrolled patients, 86 (66.7%) had pathogenic variants in PKD1 and 28 (21.7%) in PKD2, loss of function pathogenic variants in the IFT140 gene were found in 3 unrelated patients (2.3%), no pathogenic variants were found in other ADPKD genes and 12 patients (9.3%) remained genetically unresolved (ADPKD-GUR)."
    explanation: Sources the PKD1 and PKD2 counts quoted in this subtype description.
  - reference: PMID:38404363
    reference_title: "Monoallelic pathogenic IFT140 variants are a common cause of autosomal dominant polycystic kidney disease-spectrum phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this retrospective study, we tested the prevalence of the known causative genes of ADPKD-spectrum phenotype, including the PKD1, PKD2, GANAB, DNAJB11, ALG5, ALG and IFT140 genes, in a cohort of 129 ADPKD patients who consecutively underwent genetic testing in a single centre in Italy."
    explanation: Sources the cohort described here, 129 consecutively tested patients at a single Italian centre.
  - 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 relationship with ADPKD as Definitive.
- name: PKD6
  display_name: PKD6 (DNAJB11-related, ADPKD/ADTKD hybrid)
  subtype_term:
    preferred_term: polycystic kidney disease 6 with or without polycystic liver disease
    term:
      id: MONDO:0054842
      label: polycystic kidney disease 6 with or without polycystic liver disease
  genes:
  - preferred_term: DNAJB11
    term:
      id: hgnc:14889
      label: DNAJB11
  description: >-
    Monoallelic DNAJB11 variants produce a phenotypic hybrid of ADPKD and
    autosomal dominant tubulointerstitial kidney disease: normal-sized cystic
    kidneys with progressive interstitial fibrosis and late-onset end-stage
    renal disease. DNAJB11 is a co-factor of the endoplasmic-reticulum chaperone
    BiP, and the lesion is a polycystin-1 maturation and trafficking defect
    rather than loss of the channel complex.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:29706351
    reference_title: "Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD."
    explanation: Defines the DNAJB11 clinical picture stated in this subtype description.
  - reference: PMID:29706351
    reference_title: "Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins."
    explanation: Sources the BiP co-factor role stated in this subtype description.
  - reference: PMID:29706351
    reference_title: "Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD."
    explanation: Sources the polycystin-1 maturation and trafficking lesion stated in this subtype description.
  - 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 relationship with ADPKD as Definitive.
- name: PKD7
  display_name: PKD7 (ALG5-related)
  subtype_term:
    preferred_term: polycystic kidney disease 7
    term:
      id: MONDO:0031062
      label: polycystic kidney disease 7
  genes:
  - preferred_term: ALG5
    term:
      id: hgnc:20266
      label: ALG5
  description: >-
    Monoallelic ALG5 variants produce an ADPKD-spectrum disorder of multiple
    small kidney cysts, progressive interstitial fibrosis and kidney function
    decline, with few or no liver cysts. ALG5 is an endoplasmic-reticulum enzyme
    that adds glucose to the assembling N-glycan precursor, and heterozygous loss
    is enough to impair polycystin-1 maturation.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:35896117
    reference_title: "Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline."
    explanation: Defines the ALG5 clinical picture stated in this subtype description.
  - reference: PMID:35896117
    reference_title: "Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age."
    explanation: Sources the few-or-no-liver-cysts part of this subtype description.
  - reference: PMID:35896117
    reference_title: "Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors."
    explanation: Sources the enzymatic step stated in this subtype description.
  - reference: PMID:35896117
    reference_title: "Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation."
    explanation: Sources this row's statement that one defective copy is enough to impair polycystin-1 maturation.
  - 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 relationship with ADPKD as Moderate, the strength this row rests on.
- name: PKD8
  display_name: PKD8 (NEK8-related)
  subtype_term:
    preferred_term: polycystic kidney disease 8
    term:
      id: MONDO:0971178
      label: polycystic kidney disease 8
  genes:
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  description: >-
    Certain monoallelic NEK8 variants are recognized as an atypical ADPKD
    phenotype, ranging from childhood-onset kidney failure to typical ADPKD with
    few extrarenal anomalies. NEK8 is a ciliary kinase of the inversin
    compartment, so unlike the biogenesis genes the lesion is in the cilium
    itself. Biallelic NEK8 variants instead cause a syndromic renal ciliopathy,
    which is a different entity from this row.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: PMID:40677363
    reference_title: "Functional Analysis of a De Novo Monoallelic NEK8 Variant Supports Pathogenicity for a Polycystic Kidney Disease Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Recently, certain monoallelic NEK8 variants have been recognized as atypical forms of ADPKD, with phenotypes from childhood-onset kidney failure to typical ADPKD with few extrarenal anomalies."
    explanation: Sources the monoallelic NEK8 phenotype range stated in this subtype description; BACKGROUND because this letter restates the earlier cohort report.
  - reference: PMID:40677363
    reference_title: "Functional Analysis of a De Novo Monoallelic NEK8 Variant Supports Pathogenicity for a Polycystic Kidney Disease Phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Biallelic pathogenic variants in NEK8 cause syndromic renal ciliopathies."
    explanation: Sources the distinction drawn here between the monoallelic ADPKD phenotype and the biallelic syndromic ciliopathy.
  - reference: PMID:40677363
    reference_title: "Functional Analysis of a De Novo Monoallelic NEK8 Variant Supports Pathogenicity for a Polycystic Kidney Disease Phenotype."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "NEK8 localizes to the inversin compartment in cilia."
    explanation: Sources the ciliary inversin-compartment localization stated in this subtype description.
  - 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 relationship with ADPKD as Strong, scored against the parent class rather than against MONDO:0971178.
- name: ALG9-associated ADPKD
  display_name: ALG9-associated ADPKD
  subtype_term:
    preferred_term: ALG9-associated autosomal dominant polycystic kidney disease
    term:
      id: MONDO:0700000
      label: ALG9-associated autosomal dominant polycystic kidney disease
  genes:
  - preferred_term: ALG9
    term:
      id: hgnc:15672
      label: ALG9
  description: >-
    ALG9 is an endoplasmic-reticulum enzyme that adds specific mannose residues
    to the assembling N-glycan precursor, and inactivating it impairs
    polycystin-1 maturation and glycosylation. Carriers identified from a
    population cohort rather than in a clinic nonetheless had kidney cysts, and
    in a multicentre screen of individuals with polycystic kidney or liver
    disease the ALG9 kidney phenotype was mild to moderate, with lower eGFR or
    kidney failure rare.
  inheritance:
  - name: Autosomal dominant
  evidence:
  - reference: CGGV:assertion_38d817af-0a28-4453-a00f-ffccadbd9936-2023-09-11T160000.000Z
    reference_title: "ALG9 / ALG9-associated autosomal dominant polycystic kidney disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALG9 | HGNC:15672 | ALG9-associated autosomal dominant polycystic kidney disease | MONDO:0700000 | AD | Definitive"
    explanation: ClinGen grades ALG9 Definitive against this row's own MONDO class, the only one of these rows scored at the child class rather than at the ADPKD parent.
  - reference: PMID:31395617
    reference_title: "ALG9 Mutation Carriers Develop Kidney and Liver Cysts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1."
    explanation: The functional result behind the maturation defect stated in this subtype description.
  - reference: PMID:31395617
    reference_title: "ALG9 Mutation Carriers Develop Kidney and Liver Cysts."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen."
    explanation: Sources the enzymatic step stated in this subtype description.
  - reference: PMID:31395617
    reference_title: "ALG9 Mutation Carriers Develop Kidney and Liver Cysts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven of the eight (88%) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations."
    explanation: Sources this row's statement that carriers ascertained from a population cohort rather than a clinic nonetheless had kidney cysts.
  - reference: PMID:39899384
    reference_title: "Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families"
    explanation: Sources the multicentre screen referred to in this subtype description.
  - reference: PMID:39899384
    reference_title: "Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare."
    explanation: Sources the mild cystic phenotype with rare kidney failure stated in this subtype description.
  review_notes: >-
    Routing. These five rows are the gene-defined MONDO children of this entry's
    disease_term that had no home in kb/ before this change. Two of the seven
    children of MONDO:0004691 are curated as standalone entries instead,
    Polycystic_Kidney_Disease_2 for MONDO:0013131 and Polycystic_Kidney_Disease_3
    for MONDO:0010916, and those two are deliberately not duplicated as rows
    here. The five rows sit on the parent because they share one lesion with it:
    GANAB, DNAJB11, ALG5 and ALG9 each reduce the amount of mature polycystin-1
    a tubular cell achieves, which this entry models through the per-gene
    activity nodes that converge on "Impaired polycystin maturation", with ALG8
    in the same endoplasmic-reticulum set. NEK8 reduces the ciliary
    polycystin-2 content through "Reduced NEK8 p.Arg45Trp kinase activity" and
    "Variant-dependent loss of ciliary polycystin-2 localization", and IFT140
    carries a ciliary transport lesion whose route to cyst formation the cited
    cohort calls unknown, modeled as "Proposed loss of IFT140-mediated TULP3
    binding" into "IFT140-associated ciliary dysfunction". Promotion to a
    standalone entry remains open for PKD6 and PKD7 in particular, whose
    ADPKD/ADTKD-hybrid trajectory of non-enlarged kidneys with interstitial
    fibrosis differs from the parent's, on the same grounds
    Polycystic_Kidney_Disease_3 records for GANAB; the trajectory is summarized
    in each row here and is not curated as a separate progression.

mechanistic_hypotheses:
- hypothesis_group_id: canonical_pkd1_pkd2_cilia_signaling_cystogenesis_model
  hypothesis_label: Canonical PKD1/PKD2 / Primary Cilium / Cystogenesis Model
  status: CANONICAL
  description: >-
    Reduced polycystin dosage and dysregulated ciliary signaling provide the central model of
    typical PKD1/PKD2 ADPKD. Somatic PKD1/PKD2 changes in human cysts support a cellular second-hit
    component, while dosage thresholds and timing modify expression. Conditional mouse epistasis
    shows that intact cilia can promote cyst growth after polycystin loss. cAMP drives cyst
    epithelial proliferation and secretion and is therapeutically targeted by V2-receptor antagonism.
    An obligatory fluid-flow-to-ciliary-calcium sequence is not established.
  notes: >-
    The genuine falcon hypothesis exploration is consumed with primary-source qualifications:
    Kif3a/Ift20 epistasis, not Ift88 in the cited experiment; 57/63 epithelial samples and 14/24
    whole cysts in distinct end-stage cohorts, not a universal second-hit frequency. Neither
    study phases every somatic hit or observes initiation directly. Calcium imaging challenges
    one proposed sensory mechanism, not the causal importance of PKD1/PKD2. Trial efficacy supports
    targeting the vasopressin-cAMP axis without proving the entire upstream model.
  evidence:
  - reference: PMID:30042192
    reference_title: Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Pathogenic somatic mutations in PKD1/2 genes were identified in all patients and in 90%
      of cysts (57 out of 63; Supplemental Table 2, Table 2).
    explanation: >-
      Nine nephrectomy patients with end-stage disease; 57/63 sequenced cyst epithelia, not
      57/63 patients or all cysts at initiation. Constitutional and somatic variants were not
      phased.
  - reference: PMID:39702469
    reference_title: Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having
      at least one cyst with a somatic variant.
    explanation: >-
      Six PKD1-positive patients with end-stage disease; smaller whole cysts, duplicate libraries
      and unique molecular identifiers. Sampling differs from epithelial enrichment. Structural
      variants, low-frequency loss of heterozygosity and variant phase were incompletely assessed.
  - reference: PMID:23892607
    reference_title: Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      In the current study, we combined inactivation of Pkd1 and Pkd2 with loss of Kif3a and
      Ift20 to show that structurally intact cilia are required to promote rapid cyst growth
      following loss of PC1 or PC2.
    explanation: >-
      Conditional mouse epistasis supports cyst-promoting signaling through retained cilia after
      polycystin loss. Effects depend on timing and model; Kif3a and Ift20 were the cilia genes
      tested.
  - reference: PMID:27007841
    reference_title: Primary cilia are not calcium-responsive mechanosensors.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Cilia-specific Ca(2+) influxes were not observed in physiological or even highly supraphysiological
      levels of fluid flow.
    explanation: >-
      Ratiometric imaging in mouse-derived tissues and cells challenges obligatory flow-induced
      ciliary calcium influx. It does not exclude non-calcium mechanosensation or every role
      of cellular calcium.
pathophysiology:
- name: Somatic PKD1 or PKD2 inactivation in cyst epithelium
  description: >-
    Additional pathogenic somatic variants or loss of heterozygosity can further reduce polycystin
    dosage in focal cyst epithelium. Human evidence comes from end-stage nephrectomy cohorts
    and does not show that every cyst requires a detected second hit or establish its time of
    occurrence.
  genes:
  - preferred_term: PKD1
    term:
      id: hgnc:9008
      label: PKD1
  - preferred_term: PKD2
    term:
      id: hgnc:9009
      label: PKD2
  downstream:
  - target: Polycystin complex dosage loss at the renal primary cilium
    description: >-
      Additional somatic changes can reduce remaining functional polycystin dosage; allele phase
      is not resolved in the cited cohorts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:30042192
    reference_title: Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Pathogenic somatic mutations in PKD1/2 genes were identified in all patients and in 90%
      of cysts (57 out of 63; Supplemental Table 2, Table 2).
    explanation: >-
      Nine nephrectomy patients with end-stage disease; 57/63 sequenced cyst epithelia, not
      57/63 patients or all cysts at initiation. Constitutional and somatic variants were not
      phased.
  - reference: PMID:39702469
    reference_title: Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having
      at least one cyst with a somatic variant.
    explanation: >-
      Six PKD1-positive patients with end-stage disease; smaller whole cysts, duplicate libraries
      and unique molecular identifiers. Sampling differs from epithelial enrichment. Structural
      variants, low-frequency loss of heterozygosity and variant phase were incompletely assessed.
- name: Reduced GANAB glucosidase II activity
  description: Loss of GANAB reduces the catalytic glucosidase II alpha subunit that trims N-linked glycans during ER protein quality control. The activity loss is inferred from loss of gene function; residual catalytic activity has not been quantified for every heterozygous ADPKD allele.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: GANAB
    term:
      id: hgnc:4138
      label: GANAB
  molecular_functions:
  - preferred_term: Glc2Man9GlcNAc2 oligosaccharide glucosidase activity
    term:
      id: GO:0106407
      label: Glc2Man9GlcNAc2 oligosaccharide glucosidase activity
    modifier: DECREASED
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: GANAB encodes glucosidase II alpha, a protein that plays a role in trimming the glycans of glycosylated proteins
    explanation: GeneReviews identifies the enzyme and glycan-trimming function affected by GANAB loss.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Studies of PC1 have shown that its maturation and trafficking are particularly sensitive to loss of DNAJB11, glucosidase II alpha, alpha-1,2-mannosyltransferase, and dolichyl phosphate glucosyltransferase
    explanation: The review connects loss of the enzyme to PC1 maturation.
  downstream:
  - target: Impaired polycystin maturation
    description: Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Reduced DNAJB11 co-chaperone function
  description: DNAJB11 loss reduces the ER co-chaperone function involving binding immunoglobulin protein (BiP). The molecular-function binding identifies this interaction; it does not assert that each patient allele has been shown to lower intrinsic binding affinity.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DNAJB11
    term:
      id: hgnc:14889
      label: DNAJB11
  molecular_functions:
  - preferred_term: protein-folding chaperone binding
    term:
      id: GO:0051087
      label: protein-folding chaperone binding
    modifier: DECREASED
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: It is a soluble ER protein that is a co-chaperone with binding immunoglobulin protein
    explanation: GeneReviews identifies DNAJB11 as a BiP co-chaperone; the following text describes efficient folding of membrane and secreted proteins.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Studies of PC1 have shown that its maturation and trafficking are particularly sensitive to loss of DNAJB11
    explanation: The review connects loss of DNAJB11 with PC1 maturation and trafficking.
  downstream:
  - target: Impaired polycystin maturation
    description: Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Reduced ALG9 mannosyltransferase activity
  description: Loss of ALG9 compromises its alpha-1,2-mannosyltransferase contribution to N-glycosylation and subsequent membrane-protein maturation. This is a different enzymatic step from the ALG5 and ALG8 glucosyltransferase reactions.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ALG9
    term:
      id: hgnc:15672
      label: ALG9
  molecular_functions:
  - preferred_term: ALG9 alpha-1,2-mannosyltransferase activity
    term:
      id: GO:0000030
      label: mannosyltransferase activity
    modifier: DECREASED
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: ALG9 is an alpha-1,2-mannosyltransferase and is involved in the glycosylation, folding, and trafficking of membrane and secreted proteins.
    explanation: GeneReviews specifies ALG9 enzyme function and its role in membrane-protein maturation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Studies of PC1 have shown that its maturation and trafficking are particularly sensitive to loss of DNAJB11, glucosidase II alpha, alpha-1,2-mannosyltransferase, and dolichyl phosphate glucosyltransferase
    explanation: The review connects loss of ALG9 with PC1 maturation.
  downstream:
  - target: Impaired polycystin maturation
    description: Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Reduced ALG5 dolichyl-phosphate glucosyltransferase activity
  description: Reduction of ALG5 compromises dolichyl-phosphate glucosyltransferase activity in N-glycan biosynthesis, affecting PC1 maturation and localization. The gene-loss mechanism is distinguished from a direct catalytic assay of every heterozygous allele.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ALG5
    term:
      id: hgnc:20266
      label: ALG5
  molecular_functions:
  - preferred_term: dolichyl-phosphate beta-glucosyltransferase activity
    term:
      id: GO:0004581
      label: dolichyl-phosphate beta-glucosyltransferase activity
    modifier: DECREASED
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: ALG5 is a dolichyl phosphate glucosyltransferase; reduction of ALG5 disrupts N-glycosylation and affects PC1 maturation and localization.
    explanation: GeneReviews states both the enzyme function and the effect of ALG5 reduction on PC1.
  downstream:
  - target: Impaired polycystin maturation
    description: Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Reduced ALG8 second-glucose transfer activity
  description: ALG8 loss disrupts addition of the second glucose to the lipid-linked N-glycan precursor. Alg8-null renal epithelial cells have defective PC1 glycosylation and trafficking. Complete engineered loss supports the pathway but does not quantify activity loss in heterozygous human kidneys.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ALG8
    term:
      id: hgnc:23161
      label: ALG8
  molecular_functions:
  - preferred_term: dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
    term:
      id: GO:0042283
      label: dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: where ALG8 (1) catalyzes the addition of the second glucose residue.
    explanation: Figure 6 identifies the specific ALG8 enzymatic step in lipid-linked glycan synthesis.
  - reference: PMID:28375157
    reference_title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis.
    explanation: The Alg8-null cell results support impaired PC1 biogenesis; they are not assays of heterozygous patient kidneys.
  downstream:
  - target: Impaired polycystin maturation
    description: Reduced activity disrupts polycystin-1 biogenesis through the protein maturation pathway.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Reduced NEK8 p.Arg45Trp kinase activity
  description: Immunoprecipitated p.Arg45Trp NEK8 expressed in 293T cells shows reduced autophosphorylation, supporting partial loss of kinase activity for this allele. This result is not generalized to p.Ile150Met or p.Lys157Gln and does not establish dominant-negative interference in heterozygous cells. The precise causal connection to altered ciliary PC2 trafficking remains unresolved.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  molecular_functions:
  - preferred_term: protein serine/threonine kinase activity
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:37598857
    reference_title: Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: the autophosphorylation level of NEK8-p.Arg45Trp was significantly lower than NEK8-WT, suggesting that p.Arg45Trp partially loses kinase activity.
    explanation: The full-text result describes the 293T expression and immunoprecipitation assay; reduced autophosphorylation supports partial kinase impairment.
- name: Proposed loss of IFT140-mediated TULP3 binding
  description: IFT140 provides part of the TULP3-binding surface of IFT-A. Structural analysis and knockout-cell results motivate a hypothesis that IFT140 truncation disrupts TULP3-mediated cargo transport. Reduced binding in heterozygous ADPKD patient cells has not been demonstrated by these experiments, and IFT-A assembly does not require IFT140 in the reconstitution assay.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: IFT140
    term:
      id: hgnc:29077
      label: IFT140
  molecular_functions:
  - preferred_term: IFT140 binding to TULP3
    term:
      id: GO:0005515
      label: protein binding
    modifier: DECREASED
  evidence:
  - reference: PMID:36775821
    reference_title: Human IFT-A complex structures provide molecular insights into ciliary transport.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: TULP3 interacts with the TPR-like domain of IFT140 and the TPR-like and zinc finger domains of IFT122 via its N-terminal region
    explanation: The human IFT-A structure directly identifies the IFT140-TULP3 interaction.
  - reference: PMID:36775821
    reference_title: Human IFT-A complex structures provide molecular insights into ciliary transport.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: we hypothesize that one functional consequence of IFT140 truncation mutations is the disruption of TULP3-mediated cargo transport.
    explanation: The source explicitly presents the truncation-to-transport mechanism as a hypothesis; the disease-specific binding defect remains provisional.
    directness: INDIRECT
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: IFT140-associated ciliary dysfunction
    description: The proposed loss of the TULP3 interaction could compromise ciliary cargo transport; the monoallelic human mechanism remains provisional.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired polycystin maturation
  description: >-
    Disruption of endoplasmic-reticulum protein glycosylation or folding can reduce effective
    polycystin-1 maturation and trafficking. This is a shared mechanism for several minor-gene
    forms; individual proteins act at different maturation steps. ALG8 also belongs to this
    proteostasis group, although its clinical association is better established than the complete
    causal chain in patient kidneys.
  downstream:
  - target: Polycystin complex dosage loss at the renal primary cilium
    description: Defective maturation reduces delivery of functional polycystin-1.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Studies of PC1 have shown that its maturation and trafficking are particularly sensitive
      to loss of DNAJB11, glucosidase II alpha, alpha-1,2-mannosyltransferase, and dolichyl
      phosphate glucosyltransferase
    explanation: GeneReviews synthesizes experimental evidence for DNAJB11, GANAB, ALG9 and ALG5 effects on PC1 maturation.
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Eight additional genes have been suggested to cause a monoallelic ADPKD-like phenotype;
      six of these encode endoplasmic reticulum–resident, proteostasis proteins: ALG5,18 ALG6,19
      ALG8,20 ALG9,21 DNAJB11,22 and GANAB,23 plus the ciliogenesis genes, IFT140 and NEK8.24,25
    explanation: This is introductory mechanistic synthesis, not a new functional experiment in the ALG8/ALG9 clinical cohort.
- name: Variant-dependent loss of ciliary polycystin-2 localization
  description: >-
    NEK8 R45W and K157Q reduce ciliary PC2 localization when expressed in Nek8-null IMCD3 cells;
    I150M did not show this defect. This rescue assay does not itself establish dominant-negative
    interference in a heterozygous patient.
  genes:
  - preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  downstream:
  - target: Polycystin complex dosage loss at the renal primary cilium
    description: Reduced PC2 localization can impair the ciliary complex; inference from variant-specific cell assays.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:37598857
    reference_title: >-
      Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8
      can cause an autosomal dominant form of polycystic kidney disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed
      significantly decreased polycystin-2 but normal ANKS6 localization in cilia.
    explanation: >-
      Mouse renal epithelial cell rescue experiments separate ciliary localization from total
      PC2 abundance and from clinical inheritance.
- name: IFT140-associated ciliary dysfunction
  description: >-
    Monoallelic pathogenic IFT140 variants affect a ciliary transport gene and produce a distinctive
    renal cystic phenotype. The precise steps from reduced IFT140 function to the adult cyst
    pattern are incompletely resolved; it is not equated with complete cilium deletion in epistasis
    models.
  genes:
  - preferred_term: IFT140
    term:
      id: hgnc:29077
      label: IFT140
  downstream:
  - target: Renal cyst expansion
    description: >-
      Heterozygous IFT140 disease produces relatively few large renal cysts through incompletely
      resolved ciliary mechanisms.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Eight additional genes have been suggested to cause a monoallelic ADPKD-like phenotype;
      six of these encode endoplasmic reticulum–resident, proteostasis proteins: ALG5,18 ALG6,19
      ALG8,20 ALG9,21 DNAJB11,22 and GANAB,23 plus the ciliogenesis genes, IFT140 and NEK8.24,25
    explanation: This is introductory mechanistic synthesis, not a new functional experiment in the ALG8/ALG9 clinical cohort.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Heterozygous pathogenic variants in IFT140 have been identified in 66 individuals from
      38 families, with a mild PKD phenotype usually consisting of a few, larger cysts that
      can result in kidney enlargement and limited kidney insufficiency
    explanation: >-
      GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2
      progression assumptions.
- name: Polycystin complex dosage loss at the renal primary cilium
  conforms_to: renal_cystogenesis#Polycystin and Primary Cilium Signaling Loss
  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:0097731
      label: 9+0 non-motile cilium
  evidence:
  - reference: PMID:26877954
    reference_title: Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:40126492
    reference_title: 'Autosomal Dominant Polycystic Kidney Disease: A Review.'
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:30042192
    reference_title: Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Pathogenic somatic mutations in PKD1/2 genes were identified in all patients and in 90%
      of cysts (57 out of 63; Supplemental Table 2, Table 2).
    explanation: >-
      Nine nephrectomy patients with end-stage disease; 57/63 sequenced cyst epithelia, not
      57/63 patients or all cysts at initiation. Constitutional and somatic variants were not
      phased.
  - reference: PMID:39702469
    reference_title: Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having
      at least one cyst with a somatic variant.
    explanation: >-
      Six PKD1-positive patients with end-stage disease; smaller whole cysts, duplicate libraries
      and unique molecular identifiers. Sampling differs from epithelial enrichment. Structural
      variants, low-frequency loss of heterozygosity and variant phase were incompletely assessed.
  downstream:
  - target: Cilium-dependent cyst-promoting signal disinhibition
    description: Loss of polycystins permits the cilia-dependent growth response demonstrated in conditional mice.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23892607
      reference_title: Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        In the current study, we combined inactivation of Pkd1 and Pkd2 with loss of Kif3a and
        Ift20 to show that structurally intact cilia are required to promote rapid cyst growth
        following loss of PC1 or PC2.
      explanation: >-
        Conditional mouse epistasis supports cyst-promoting signaling through retained cilia
        after polycystin loss. Effects depend on timing and model; Kif3a and Ift20 were the
        cilia genes tested.
  - target: Increased renal epithelial cAMP signaling
    description: >-
      Polycystin dysfunction is associated with altered cAMP regulation; the intervening calcium
      events are context-dependent.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced epithelial fatty acid oxidation
    description: >-
      Pkd1 deficiency reduces fatty acid oxidation in paired mouse renal epithelial cell lines;
      mediating steps remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cilium-dependent cyst-promoting signal disinhibition
  description: >-
    With reduced polycystin function and retained cilia, a cyst-promoting signal is derepressed
    in conditional mouse models. Its molecular identity remains incompletely defined; the magnitude
    depends on developmental timing and the interval between polycystin loss and cilia involution.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  cellular_components:
  - preferred_term: primary cilium
    term:
      id: GO:0097731
      label: 9+0 non-motile cilium
  evidence:
  - reference: PMID:23892607
    reference_title: Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      In the current study, we combined inactivation of Pkd1 and Pkd2 with loss of Kif3a and
      Ift20 to show that structurally intact cilia are required to promote rapid cyst growth
      following loss of PC1 or PC2.
    explanation: >-
      Conditional mouse epistasis supports cyst-promoting signaling through retained cilia after
      polycystin loss. Effects depend on timing and model; Kif3a and Ift20 were the cilia genes
      tested.
  downstream:
  - target: Renal epithelial proliferation
    description: >-
      Reduced proliferation accompanies suppression of cyst growth after cilia removal; the
      responsible signal is not uniformly explained by MAPK, cAMP or mTOR.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23892607
      reference_title: Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        The rates of proliferation in the cilia-polycystin double mutants were significantly
        reduced compared to the respective polycystin-only mutants and correlated with relative
        cyst severity in early onset Pkhd1-cre-based models (Fig. 4a-d).
      explanation: >-
        Ki67/BrdU measurements in conditional mouse collecting-duct cysts, with adult-inducible
        experiments showing related effects.
- name: Altered cellular calcium signaling
  description: >-
    Reduced cellular calcium signaling is one proposed contributor to cAMP dysregulation after
    polycystin dysfunction. The specific assertion that flow first evokes a ciliary calcium
    influx is contested and is not a required step in the represented causal chain.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  evidence:
  - reference: PMID:26877954
    reference_title: Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:27007841
    reference_title: Primary cilia are not calcium-responsive mechanosensors.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Cilia-specific Ca(2+) influxes were not observed in physiological or even highly supraphysiological
      levels of fluid flow.
    explanation: >-
      Ratiometric imaging in mouse-derived tissues and cells challenges obligatory flow-induced
      ciliary calcium influx. It does not exclude non-calcium mechanosensation or every role
      of cellular calcium.
- name: Increased renal epithelial cAMP signaling
  conforms_to: renal_cystogenesis#cAMP and Vasopressin-V2R Signaling Activation
  description: >-
    Elevated renal epithelial cAMP and PKA activity promote cyst expansion. Vasopressin V2-receptor
    signaling is a clinically actionable input; altered calcium-dependent adenylate cyclase
    and phosphodiesterase regulation is a proposed additional input rather than a universal
    initiating sequence.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  evidence:
  - reference: PMID:26877954
    reference_title: Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:26877954
    reference_title: Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Renal epithelial proliferation
    description: cAMP/PKA can promote proliferative signaling in cystic epithelium.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Chloride-driven cyst fluid secretion
    description: cAMP/PKA promotes epithelial chloride transport and fluid secretion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Renal epithelial proliferation
  conforms_to: renal_cystogenesis#Cyst-Lining Epithelial Proliferation and Transepithelial Fluid Secretion
  description: >-
    Increased proliferation of cyst-lining tubular epithelial cells enlarges the epithelial
    surface of developing cysts.
  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
  evidence:
  - reference: PMID:26877954
    reference_title: Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Renal cyst expansion
    description: Growth of the epithelial lining contributes to expanding cysts.
    causal_link_type: DIRECT
- name: Chloride-driven cyst fluid secretion
  description: Chloride transport by cyst-lining epithelium promotes fluid accumulation within the cyst lumen.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: chloride transmembrane transport
    term:
      id: GO:1902476
      label: chloride transmembrane transport
    modifier: INCREASED
  downstream:
  - target: Renal cyst expansion
    description: Transepithelial fluid secretion increases cyst volume.
    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: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
- name: Renal cyst expansion
  conforms_to: renal_cystogenesis#Progressive Cyst Expansion and Kidney Enlargement
  description: >-
    Progressive epithelial cyst enlargement increases total kidney volume and distorts surrounding
    tubules and vessels in typical ADPKD. Minor-gene forms can show small cysts or fibrosis
    without marked enlargement.
  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: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Renal parenchymal injury and fibrosis
    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: OTHER
      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.
      quote_role: REVIEW_SYNTHESIS
  - target: Renal cysts
    causal_link_type: DIRECT
  - target: Hematuria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Flank pain
    causal_link_type: DIRECT
  - target: Recurrent urinary tract infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Enlarged kidney
    causal_link_type: DIRECT
  - target: Uric acid nephrolithiasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Calcium oxalate nephrolithiasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pyelonephritis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Renal vascular resistance increase
    description: Cyst-associated vascular distortion contributes to abnormal renal hemodynamics.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired renal concentrating ability
    description: Tubular dysfunction produces an early concentrating defect, which may precede reduced GFR.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Renal parenchymal injury and fibrosis
  conforms_to: renal_cystogenesis#Nephron Loss and Progressive Kidney Failure
  description: >-
    Cyst-associated tissue remodeling, extracellular-matrix accumulation and fibrosis reduce
    functioning renal parenchyma. This tissue injury underlies declining filtration and eventual
    kidney failure in progressive disease.
  evidence:
  - reference: PMID:26877954
    reference_title: Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  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
  - target: Renal insufficiency
    causal_link_type: DIRECT
  - target: Decreased glomerular filtration rate
    causal_link_type: DIRECT
  - target: Elevated circulating creatinine concentration
    causal_link_type: DIRECT
  - target: Albuminuria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal urinary electrolyte concentration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Renal vascular resistance increase
  description: >-
    Abnormal renal hemodynamics and renin-angiotensin activity contribute to early hypertension,
    often before GFR declines.
  downstream:
  - target: Hypertension
    description: Increased renal vascular resistance and altered sodium handling contribute to elevated blood pressure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Hypertension often develops in young adults, and even in childhood, and usually before any decline in GFR.
    explanation: >-
      GeneReviews places hypertension before filtration loss and describes increased vascular
      resistance and normal or high renin activity.
- name: Reduced epithelial fatty acid oxidation
  description: >-
    Pkd1-deficient mouse renal epithelial cell lines show reduced fatty acid oxidation. The
    same study did not find increased glycolysis, and human therapeutic relevance remains unproven.
  evidence:
  - reference: PMID:27077126
    reference_title: Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: We found that renal epithelial cells lacking Pkd1 have cell autonomous defects in fatty acid oxidation.
    explanation: >-
      Paired immortalized mouse renal epithelial cell lines; the bulk kidney metabolomic signature
      is a separate model-organism observation.
  - reference: PMID:27077126
    reference_title: Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Changes in glycolysis were not observed (Fig. 3, c and d, and Supplementary Figure S5).
    explanation: This experiment does not support a universal switch to increased glycolysis.
- name: Hepatic epithelial cyst expansion
  description: >-
    Polycystin dysfunction also affects hepatic cyst epithelium. Cyst growth can produce an
    extensive liver burden, but symptomatic hepatomegaly is much less common than imaging-detected
    liver cysts.
  genes:
  - preferred_term: PKD1
    term:
      id: hgnc:9008
      label: PKD1
  - preferred_term: PKD2
    term:
      id: hgnc:9009
      label: PKD2
  downstream:
  - target: Hepatic cysts
    description: Hepatic cyst expansion produces imaging-detectable cysts.
    causal_link_type: DIRECT
  - target: Polycystic liver disease
    description: Extensive hepatic cyst burden produces PLD.
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The prevalence of liver cysts increases with age and occasionally results in clinically
      significant severe polycystic liver disease (PLD), most often in females.
    explanation: GeneReviews distinguishes age-dependent liver cysts from severe symptomatic PLD.
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
- name: Vascular polycystin dysfunction
  description: >-
    Reduced polycystin function at vascular sites is implicated in arterial complications. The
    tissue mechanisms are less resolved than the renal epithelial pathway and are not effects
    of renal-cell cilia on every extrarenal organ.
  genes:
  - preferred_term: PKD1
    term:
      id: hgnc:9008
      label: PKD1
  - preferred_term: PKD2
    term:
      id: hgnc:9009
      label: PKD2
  downstream:
  - target: Cerebral arterial dilatation
    description: Vascular polycystin dysfunction is implicated in cerebral arterial abnormalities.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Aortic root aneurysm
    description: An incompletely defined arterial-wall process contributes to aortic complications.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal systemic arterial morphology
    description: Broader arterial changes are reported; intermediates remain unspecified.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The localization of polycystins to other phenotypic sites (e.g., the vascular system)
      indicates that reductions in the level of these proteins underlie disease complications
      such as intracranial aneurysms
    explanation: GeneReviews provides the vascular-site hypothesis; molecular intermediates remain incompletely defined.
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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000107 | Renal cyst | Very frequent (99-80%)
    explanation: Orphanet lists renal cysts as very frequent in ADPKD.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000083 | Renal insufficiency | Very frequent (99-80%)
    explanation: Orphanet lists renal insufficiency as very frequent.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0012213 | Decreased glomerular filtration rate | Very frequent (99-80%)
    explanation: Orphanet lists decreased GFR as very frequent.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    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.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    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: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The prevalence of liver cysts increases with age and occasionally results in clinically
      significant severe polycystic liver disease (PLD), most often in females.
    explanation: GeneReviews distinguishes age-dependent liver cysts from severe symptomatic PLD.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    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: OTHER
    snippet: Hypertension affects 70% to 80% of patients with ADPKD
    explanation: The 2025 review quantitatively supports hypertension as a common feature.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Hypertension often develops in young adults, and even in childhood, and usually before any decline in GFR.
    explanation: GeneReviews supports early onset, which is not captured by a cross-sectional catalog frequency.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000790 | Hematuria | Frequent (79-30%)
    explanation: Orphanet lists hematuria as frequent.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0012622 | Chronic kidney disease | Frequent (79-30%)
    explanation: Orphanet lists chronic kidney disease as frequent.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    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: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Approximately 50% of individuals with ADPKD have end-stage kidney disease (ESKD) by age 60 years.
    explanation: Historical aggregate natural history summarized by GeneReviews; gene and variant class strongly modify prognosis.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0030157 | Flank pain | Frequent (79-30%)
    explanation: Orphanet lists flank pain as frequent.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0012592 | Albuminuria | Frequent (79-30%)
    explanation: Orphanet lists albuminuria as frequent.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0012591 | Abnormal urinary electrolyte concentration | Frequent (79-30%)
    explanation: Orphanet lists this urinary electrolyte abnormality as frequent.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000010 | Recurrent urinary tract infections | Occasional (29-5%)
    explanation: Orphanet lists recurrent urinary tract infections as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- category: Renal
  name: Enlarged kidney
  frequency: OCCASIONAL
  description: >-
    Kidney enlargement is characteristic of typical PKD1/PKD2 disease and varies with age and
    cyst burden. DNAJB11 and some other minor-gene forms can progress without enlarged kidneys.
  phenotype_term:
    preferred_term: Enlarged kidney
    term:
      id: HP:0000105
      label: Enlarged kidney
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000105 | Enlarged kidney | Occasional (29-5%)
    explanation: Orphanet lists enlarged kidney as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000791 | Uric acid nephrolithiasis | Occasional (29-5%)
    explanation: Orphanet lists uric acid nephrolithiasis as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0008672 | Calcium oxalate nephrolithiasis | Occasional (29-5%)
    explanation: Orphanet lists calcium oxalate nephrolithiasis as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0012330 | Pyelonephritis | Occasional (29-5%)
    explanation: Orphanet lists pyelonephritis as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- category: Hepatic
  name: Polycystic liver disease
  frequency: OCCASIONAL
  description: >-
    Extensive liver cyst disease ranges from asymptomatic involvement to severe volume-related
    symptoms, especially in women; liver synthetic function is usually preserved. A catalog
    PLD band should not be interpreted as the prevalence of symptomatic disease.
  phenotype_term:
    preferred_term: Polycystic liver disease
    term:
      id: HP:0006557
      label: Polycystic liver disease
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0006557 | Polycystic liver disease | Occasional (29-5%)
    explanation: Orphanet lists polycystic liver disease as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0001737 | Pancreatic cysts | Occasional (29-5%)
    explanation: Orphanet lists pancreatic cysts as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0001634 | Mitral valve prolapse | Occasional (29-5%)
    explanation: Orphanet lists mitral valve prolapse as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0002616 | Aortic root aneurysm | Occasional (29-5%)
    explanation: Orphanet lists aortic root aneurysm as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- category: Neurological
  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
    reference_title: Autosomal dominant polycystic kidney disease
    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: OTHER
    snippet: approximately 9% to 14% develop intracranial aneurysms
    explanation: The review quantifies intracranial aneurysm risk in ADPKD.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Overall, the prevalence of intracranial aneurysms is fivefold higher than in the general
      population and further increased in those with a positive family history of aneurysms
      or subarachnoid hemorrhage.
    explanation: GeneReviews documents the vascular risk and its familial enrichment.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
    The source names intracranial aneurysms without specifying every aneurysm morphology; the
    broader arterial-dilatation binding is retained rather than assuming every lesion is a berry
    aneurysm.
- 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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0011004 | Abnormal systemic arterial morphology | Occasional (29-5%)
    explanation: Orphanet lists abnormal systemic arterial morphology as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- category: Neurological
  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
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0100702 | Arachnoid cyst | Occasional (29-5%)
    explanation: Orphanet lists arachnoid cyst as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- category: Endocrine
  name: Pituitary growth hormone cell adenoma
  frequency: VERY_RARE
  description: >-
    Orphanet catalogs a very rare association. The reviewed clinical baseline does not establish
    a causal ADPKD-to-pituitary-adenoma pathway; no such edge is asserted.
  phenotype_term:
    preferred_term: Pituitary growth hormone cell adenoma
    term:
      id: HP:0011760
      label: Pituitary growth hormone cell adenoma
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- category: Reproductive
  name: Reduced sperm motility
  frequency: OCCASIONAL
  description: Abnormal sperm motility has been reported, but this does not establish excess male infertility across ADPKD.
  phenotype_term:
    preferred_term: Reduced sperm motility
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0012207 | Reduced sperm motility | Occasional (29-5%)
    explanation: Orphanet lists reduced sperm motility as occasional.
  notes: >-
    Orphanet frequency is a catalog annotation without an age, genotype or ascertainment denominator
    in the cached record; it is not a lifetime penetrance estimate for every ADPKD genotype.
- name: Impaired renal concentrating ability
  category: Renal
  description: An early tubular concentrating defect may be present before reduced glomerular filtration.
  phenotype_term:
    preferred_term: Impaired renal concentrating ability
    term:
      id: HP:0004727
      label: Impaired renal concentrating ability
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Reduction in urinary concentrating capacity and excretion of ammonia occur early in individuals with ADPKD.
    explanation: GeneReviews describes early functional tubular abnormalities.
- name: Hernia of the abdominal wall
  category: Gastrointestinal
  description: >-
    Abdominal wall hernias are an associated extrarenal manifestation; their precise relation
    to connective-tissue properties and organ enlargement is not resolved here.
  phenotype_term:
    preferred_term: Hernia of the abdominal wall
    term:
      id: HP:0004299
      label: Hernia of the abdominal wall
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane;
      dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse;
      and abdominal wall hernias.
    explanation: GeneReviews clinical characteristics include abdominal wall hernias.
- name: Seminal vesicle cysts
  category: Reproductive
  description: Common imaging findings in males; cyst presence alone does not establish infertility.
  phenotype_term:
    preferred_term: Seminal vesicle cyst
    term:
      id: HP:6000191
      label: Seminal vesicle cyst
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Seminal vesicle cysts, present in 40% of males, rarely result in infertility.
    explanation: GeneReviews provides a male-specific estimate; KDIGO 2025 cautions against inferring excess infertility.
- name: Bronchiectasis
  category: Respiratory
  description: >-
    KDIGO summarizes bronchiectasis in 19–37% of imaged cohorts, usually as an incidental radiologic
    finding with little clinical significance; this is not a population-screening estimate.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Bronchiectasis 19 –37 Incidental radiologic ﬁnding, typically of no clinical signi ﬁcance
    explanation: Guideline table 4 reports an imaging association rather than symptomatic respiratory disease.
biochemical:
- name: Creatinine
  presence: INCREASED
  context: Circulating creatinine increases as glomerular filtration declines.
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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
    reference_title: Autosomal dominant polycystic kidney disease
    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: >-
    Major cause of typical ADPKD. Truncating variants generally confer earlier kidney failure
    than nontruncating/hypomorphic variants; some hypomorphic alleles show reduced penetrance.
    Germline dosage, mosaicism and somatic changes influence severity.
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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: OTHER
    snippet: primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes.
    explanation: The review identifies PKD1 as the major causal gene.
    quote_role: REVIEW_SYNTHESIS
  - 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.
  - reference: PMID:30042192
    reference_title: Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Pathogenic somatic mutations in PKD1/2 genes were identified in all patients and in 90%
      of cysts (57 out of 63; Supplemental Table 2, Table 2).
    explanation: >-
      Nine nephrectomy patients with end-stage disease; 57/63 sequenced cyst epithelia, not
      57/63 patients or all cysts at initiation. Constitutional and somatic variants were not
      phased.
  - reference: PMID:39702469
    reference_title: Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having
      at least one cyst with a somatic variant.
    explanation: >-
      Six PKD1-positive patients with end-stage disease; smaller whole cysts, duplicate libraries
      and unique molecular identifiers. Sampling differs from epithelial enrichment. Structural
      variants, low-frequency loss of heterozygosity and variant phase were incompletely assessed.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The average age at onset of ESKD in affected individuals with truncating PKD1 variants
      is 55.6 years compared to 67.9 years
    explanation: GeneReviews summarizes variant-class-dependent prognosis; these are cohort averages, not individual predictions.
- name: PKD2 pathogenic variants
  gene_term:
    preferred_term: PKD2
    term:
      id: hgnc:9009
      label: PKD2
  association: CAUSATIVE
  features: >-
    A major causal gene, usually associated with later kidney failure than PKD1. Adult imaging
    can be less sensitive at younger ages; a negative early scan does not reliably exclude every
    PKD2 variant.
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - 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: >-
    Heterozygous variants often cause mild renal cystic disease with liver cysts; some families
    have predominantly severe liver disease and few renal cysts.
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Pathogenic variants cause mild cystic kidney disease, usually without a decline in kidney
      function, with the majority of affected individuals having liver cysts
    explanation: >-
      GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2
      progression assumptions.
- name: DNAJB11 pathogenic loss-of-function variants
  gene_term:
    preferred_term: DNAJB11
    term:
      id: hgnc:14889
      label: DNAJB11
  association: CAUSATIVE
  features: >-
    Heterozygous variants cause small bilateral cysts, often without kidney enlargement, with
    later interstitial fibrosis and kidney insufficiency; this overlaps the ADTKD phenotype.
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The phenotype is quite consistent and results in the development of small, bilateral kidney
      cysts, usually without kidney enlargement
    explanation: >-
      GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2
      progression assumptions.
- name: IFT140 pathogenic loss-of-function variants
  gene_term:
    preferred_term: IFT140
    term:
      id: hgnc:29077
      label: IFT140
  association: CAUSATIVE
  features: >-
    Monoallelic pathogenic variants usually produce a few large renal cysts with limited renal
    insufficiency and rare liver cysts. Biallelic syndromic IFT140 disease is a distinct context.
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Heterozygous pathogenic variants in IFT140 have been identified in 66 individuals from
      38 families, with a mild PKD phenotype usually consisting of a few, larger cysts that
      can result in kidney enlargement and limited kidney insufficiency
    explanation: >-
      GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2
      progression assumptions.
- name: ALG5 pathogenic variants
  gene_term:
    preferred_term: ALG5
    term:
      id: hgnc:20266
      label: ALG5
  association: CAUSATIVE
  features: >-
    Heterozygous variants can produce non-enlarged cystic kidneys, interstitial fibrosis and
    late kidney failure, with few liver cysts.
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The typical phenotype is non-enlarged cystic kidneys and interstitial fibrosis with few
      liver cysts leading to ESKD in older individuals.
    explanation: >-
      GeneReviews provides the gene-specific phenotype and prevents transferring typical PKD1/PKD2
      progression assumptions.
- name: ALG9 pathogenic loss-of-function variants
  gene_term:
    preferred_term: ALG9
    term:
      id: hgnc:15672
      label: ALG9
  association: CAUSATIVE
  features: >-
    Monoallelic pathogenic loss-of-function variants usually cause milder cystic kidney disease,
    with variable liver involvement and incomplete clinical penetrance. Clinical referral cohorts
    overrepresent severe disease compared with genotype-first cohorts.
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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.
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.
    explanation: >-
      Primary clinical and genotype-first cohorts support the gene-disease relationship while
      showing limited penetrance for clinically important kidney dysfunction. The clinical cohort
      included 51 ALG8 and 23 ALG9 families among 3935 referrals.
- name: NEK8 kinase-domain missense variants
  gene_term:
    preferred_term: NEK8
    term:
      id: hgnc:13387
      label: NEK8
  association: CAUSATIVE
  features: >-
    Specific heterozygous kinase-domain missense variants cause ADPKD-spectrum disease: R45W
    in ten families, K157Q and I150M in one each in a 21-person series. R45W/K157Q often presented
    early; I150M was later and did not share the PC2-trafficking defect in the rescue assay.
    A dominant-negative mechanism is proposed, not established for all variants; biallelic NEK8
    syndromic disease is distinct.
  evidence:
  - reference: ORPHA:730
    reference_title: Autosomal dominant polycystic kidney disease
    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.
  - reference: PMID:37598857
    reference_title: >-
      Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8
      can cause an autosomal dominant form of polycystic kidney disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease
      (mostly neonatal) without consistent extra-kidney manifestations.
    explanation: >-
      Twelve families with specific kinase-domain missense variants; not evidence that all heterozygous
      NEK8 loss-of-function alleles cause this phenotype.
- name: ALG8 pathogenic variants
  gene_term:
    preferred_term: ALG8
    term:
      id: hgnc:23161
      label: ALG8
  association: CAUSATIVE
  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.
  - reference: PMID:39899384
    reference_title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.
    explanation: >-
      Primary clinical and genotype-first cohorts support the gene-disease relationship while
      showing limited penetrance for clinically important kidney dysfunction. The clinical cohort
      included 51 ALG8 and 23 ALG9 families among 3935 referrals.
  features: >-
    Monoallelic pathogenic variants, predominantly loss of function, cause a variably penetrant
    cystic kidney/liver spectrum. Severe typical ADPKD is uncommon and warrants assessment for
    additional causes. This entry includes its renal spectrum; isolated liver disease also occurs.
treatments:
- name: Tolvaptan vasopressin V2 receptor antagonist therapy
  description: >-
    Tolvaptan slows kidney-volume growth and eGFR decline in selected adults with rapidly progressive
    ADPKD. KDIGO 2025 recommends initiation with eGFR at least 25 mL/min/1.73 m2 and documented
    rapid-progression risk; decisions above age 55 are individualized. Aquaresis requires reliable
    water access and interruption during volume depletion. Liver toxicity requires baseline
    and regular monitoring under local prescribing requirements. Trial eGFR benefits are not
    direct observations of a delay in dialysis.
  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: Increased renal epithelial cAMP signaling
    treatment_effect: INHIBITS
    description: Vasopressin V2 receptor antagonism lowers the cAMP drive that supports cyst epithelial proliferation and secretion.
    evidence:
    - reference: PMID:26877954
      reference_title: Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      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: Mechanistic review supports the targeted cAMP pathway; randomized outcomes establish efficacy separately.
    - reference: PMID:23121377
      reference_title: Tolvaptan in patients with autosomal dominant polycystic kidney disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: >-
        Studies of animal models implicate the antidiuretic hormone arginine vasopressin and
        its second messenger adenosine-3′,5′-cyclic monophosphate (cAMP) as promoters of kidney-cyst
        cell proliferation and luminal fluid secretion.
      explanation: >-
        The TEMPO trial introduction summarizes the preclinical vasopressin-cAMP rationale;
        it is not a human mechanistic measurement.
  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: >-
      TEMPO 3:4 randomized 1445 adults aged 18–50 with total kidney volume at least 750 mL and
      preserved creatinine clearance. TKV increased 2.8% versus 5.5% yearly; discontinuation
      was 23% versus 14%. The full text reports aquaretic adverse effects and liver enzyme elevations.
  - reference: PMID:40126492
    reference_title: 'Autosomal Dominant Polycystic Kidney Disease: A Review.'
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:29105594
    reference_title: Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 (95%
      confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61
      ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group
    explanation: >-
      REPRISE primary endpoint over one year after a tolerability run-in; 1370 randomized, with
      1331 contributing to the primary analysis. The run-in selected patients able to tolerate
      treatment.
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We recommend initiating tolvaptan treatment in adults with ADPKD with an eGFR $25 ml/min/1.73
      m 2 who are at risk for rapidly progressive disease.
    explanation: >-
      KDIGO 2025 recommendation; the PDF text extraction encodes the at-least symbol as a dollar
      sign. The threshold is at least 25 mL/min/1.73 m2.
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Frequent monitoring (monthly for the ﬁrst 18 months, and then every 3 months until drug
      discontinuation) of LFTs is mandatory in people treated with tolvaptan for ADPKD.
    explanation: KDIGO monitoring guidance; local regulatory schedules and product information govern prescribing.
  therapeutic_modality: SMALL_MOLECULE
- name: ACE inhibitor or angiotensin receptor blocker therapy
  description: >-
    Use an ACE inhibitor or an ARB as first-line blood-pressure therapy; avoid routine dual
    blockade. KDIGO targets differ by age, CKD stage and measurement method: in hypertensive
    adults aged 18–49 with G1–G2, home BP at or below 110/75 mm Hg if tolerated; at age 50 or
    above and/or G3–G5, standardized office systolic BP below 120 if tolerated. HALT-PKD reduced
    kidney-volume growth with intensive control but did not show an overall eGFR benefit.
  treatment_term:
    preferred_term: ACE inhibitor or angiotensin receptor blocker therapy
    term:
      id: NCIT:C172184
      label: Antihypertensive Therapy
    therapeutic_agent:
    - preferred_term: ACE Inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: Angiotensin II Receptor Antagonist
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Treatment for hypertension may include ACE inhibitors or angiotensin II receptor blockers and diet modification.
    explanation: GeneReviews supports renin-angiotensin blockade.
  - reference: PMID:25399733
    reference_title: Blood pressure in early autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure
      group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006)
    explanation: >-
      HALT-PKD enrolled younger hypertensive participants with preserved eGFR; the volume endpoint
      does not establish an overall eGFR benefit or a benefit from dual blockade.
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      For those aged $50 years and/or with CKD G3 –G5, we recommend a target mean systolic blood
      pressure of <120 mm Hg, if tolerated, assessed using standardized of ﬁce BP measurement.
    explanation: >-
      PDF extraction renders the at-least sign as a dollar sign; the clinical target refers
      to age 50 or above and/or CKD G3–G5, using standardized office measurement.
  - reference: PMID:25399733
    reference_title: Blood pressure in early autosomal dominant polycystic kidney disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A beneficial effect on cyst burden (rate of total kidney-volume growth) was not associated
      with an improvement in the slope of the estimated GFR.
    explanation: 'HALT-PKD full-text interpretation: TKV and eGFR outcomes must not be conflated.'
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: We recommend avoiding any combination of ACEi, ARB, and direct renin- inhibitor therapy.
    explanation: KDIGO recommends single-system blockade rather than combining these drug classes.
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Based on available RCT results, we recommend a target BP of #110/75 mm Hg, as measured by home BP-monitoring, if tolerated, for people aged 18 –49 years with CKD G1 –G2 and BP >130/85 mm Hg."
    explanation: >-
      KDIGO younger-adult target; the PDF extraction encodes the at-most symbol as a hash. This
      is home BP, unlike the standardized office target for older or more advanced CKD.
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
- name: Dietary sodium restriction
  description: >-
    Moderate sodium restriction, generally below 2000 mg/day, is part of blood-pressure and
    CKD management. It is not interchangeable with pharmacologic blood-pressure control or established
    as a stand-alone cure for cystogenesis.
  treatment_term:
    preferred_term: dietary sodium intake avoidance
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  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: OTHER
    snippet: dietary sodium restriction (<2000 mg/d)
    explanation: This directly supports sodium restriction as a treatment component.
    quote_role: REVIEW_SYNTHESIS
  therapeutic_modality: BEHAVIORAL
- name: Genetic counseling
  description: >-
    Counsel about variable expression, a 50% transmission risk for a heterozygous familial variant,
    cascade testing of adults, and prenatal or preimplantation testing when the familial variant
    is known. Childhood testing is a shared decision with the family and appropriate specialists;
    absence of symptoms does not establish absence of disease.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Once the ADPKD-causing pathogenic variant has been identified in an affected family member,
      prenatal and preimplantation genetic testing are possible.
    explanation: GeneReviews genetic counseling supports reproductive testing options.
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Expert counseling about diagnostic options, delivered by a team that includes a pediatric
      nephrologist and a geneticist, should be offered.
    explanation: KDIGO recommends shared decisions about diagnosis in at-risk children, updating older categorical approaches.
- name: Individualized kidney pain management
  description: >-
    Investigate acute pain for hemorrhage, stones or infection. Persistent pain is managed stepwise
    with noninvasive measures and individualized analgesia; selected refractory cases require
    specialist cyst-directed procedures or nerve interventions. Long-term nephrotoxic analgesic
    exposure should be avoided.
  treatment_term:
    preferred_term: Individualized kidney pain management
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Conservative treatment of flank pain includes nonopioid agents, tricyclic antidepressants,
      narcotic analgesics, and splanchnic nerve blockade.
    explanation: GeneReviews supplies management options; choice requires renal-function and adverse-effect assessment.
  target_phenotypes:
  - preferred_term: Flank pain
    term:
      id: HP:0030157
      label: Flank pain
- name: Treatment of kidney cyst infection
  description: >-
    Culture-guided antibiotics with adequate cyst penetration are required for suspected or
    confirmed kidney cyst infection, typically for 4–6 weeks under KDIGO guidance. This duration
    should not be transferred to uncomplicated lower urinary infection. Drug selection must
    consider susceptibility, renal function and adverse effects.
  treatment_term:
    preferred_term: Treatment of kidney cyst infection
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  evidence:
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A lipid-soluble antibiotic (e.g., trimethoprim- sulfamethoxazole, ﬂuoroquinolone) may
      have better pene- tration into the cysts, and should be used if possible.
    explanation: >-
      KDIGO kidney-cyst infection guidance; adjacent full text specifies 4–6 weeks and cautions
      about fluoroquinolone adverse effects.
  therapeutic_modality: SMALL_MOLECULE
- name: Dialysis for kidney failure
  description: >-
    Provide kidney replacement therapy when clinically indicated; modality is individualized
    according to residual function, organ enlargement and patient preference.
  treatment_term:
    preferred_term: Dialysis for kidney failure
    term:
      id: NCIT:C15221
      label: Dialysis
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: ESKD is treated with dialysis and transplantation.
    explanation: GeneReviews management of kidney failure.
  target_phenotypes:
  - preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
- name: Kidney transplantation
  description: >-
    Transplantation is the preferred replacement option for suitable candidates, with preemptive
    transplantation when feasible. Related donors require careful exclusion of familial disease;
    native nephrectomy is reserved for selected indications.
  treatment_term:
    preferred_term: Kidney transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: ESKD is treated with dialysis and transplantation.
    explanation: GeneReviews management of kidney failure.
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
- name: Somatostatin analogue therapy for symptomatic polycystic liver disease
  description: >-
    Long-acting somatostatin analogues may be used for marked cystic hepatomegaly with severe
    volume-related symptoms in expert care. Assess benefit after 6–12 months and discontinue
    without benefit. This is a liver-volume/symptom indication, not proof of preserved kidney
    function or a recommendation for every asymptomatic liver cyst.
  treatment_term:
    preferred_term: Somatostatin analogue therapy for symptomatic polycystic liver disease
    term:
      id: NCIT:C15449
      label: Somatostatin Analog Therapy
  evidence:
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We recommend prescribing long-acting somatostatin analogues in people with marked cystic
      hepatomegaly in PLD with severe volume-related symptoms.
    explanation: >-
      KDIGO 2025 integrates four randomized trials showing reduced liver-volume growth; evaluate
      symptoms and volume response.
  target_phenotypes:
  - preferred_term: Polycystic liver disease
    term:
      id: HP:0006557
      label: Polycystic liver disease
- name: Specialist intervention for severe polycystic liver disease
  description: >-
    Selected symptomatic patients may require aspiration/sclerotherapy, fenestration, resection
    or transplantation according to cyst distribution, liver volume and local expertise. These
    procedures are not indicated solely because liver cysts are visible.
  treatment_term:
    preferred_term: Specialist intervention for severe polycystic liver disease
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Severe symptoms may require percutaneous aspiration and sclerosis, laparoscopic fenestration,
      combined hepatic resection and cyst fenestration, liver transplantation, or selective
      hepatic artery embolization.
    explanation: >-
      GeneReviews describes options for severe liver symptoms; KDIGO 2025 emphasizes expert
      centers and individualized selection.
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Polycystic liver disease
    term:
      id: HP:0006557
      label: Polycystic liver disease
- name: Avoidance of nephrotoxic and liver-cyst-promoting exposures
  description: >-
    Avoid long-term nephrotoxic analgesic use, smoking and high-salt intake. In substantial
    PLD, discuss estrogen exposure and contraceptive or hormone-treatment alternatives with
    clinicians because estrogen can promote liver cyst growth.
  treatment_term:
    preferred_term: ADPKD risk-reduction counseling
    term:
      id: NCIT:C61547
      label: Counseling
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Long-term administration of nephrotoxic agents, high levels of caffeine, high-salt diet,
      smoking, and obesity, and in individuals with severe PLD, use of estrogens and possibly
      progestogens.
    explanation: GeneReviews agents/circumstances to avoid; estrogen counseling is reinforced by KDIGO 2025.
diagnosis:
- name: Age- and family-history-specific kidney imaging
  description: >-
    In individuals with an affected first-degree relative and typical PKD1/PKD2 risk, ultrasound
    criteria include at least three total renal cysts at age 15–39, at least two in each kidney
    at 40–59, and at least four in each kidney at age 60 or above. MRI can resolve equivocal
    cases. A negative scan in a younger relative does not exclude all genotypes; criteria for
    incidental cysts without family history and for minor genes require separate assessment.
  diagnosis_term:
    preferred_term: Age- and family-history-specific kidney imaging
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of ADPKD is established in a proband with age-specific kidney imaging criteria
      and either an affected first-degree relative with ADPKD or a heterozygous pathogenic variant
      in PKD1, PKD2, or one of the less common associated genes (ALG5, ALG9, DNAJB11, GANAB,
      IFT140) identified by molecular genetic testing.
    explanation: GeneReviews establishes imaging plus family/genetic context.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The presence of three or more (unilateral or bilateral) kidney cysts in an individual age 15-39 years
    explanation: GeneReviews gives age-specific ultrasound criteria in a relative at 50% risk.
- name: Molecular confirmation and familial testing
  description: >-
    Use a cystic-kidney multigene assay appropriate to the phenotype. PKD1 pseudogene homology,
    copy-number variation and low-level mosaicism need assay-specific coverage; a negative routine
    panel or a variant of uncertain significance does not establish or exclude every form. Test
    a known familial pathogenic variant when evaluating relatives or related donors.
  diagnosis_term:
    preferred_term: Molecular confirmation and familial testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Multigene panels using next-generation sequencing should be carefully designed to maximize
      identification of a PKD1 pathogenic variant, which is complicated by several highly homologous
      pseudogenes
    explanation: GeneReviews explains a major assay-design limitation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Specific analysis is required to detect exon or whole-gene deletions/duplications.
    explanation: Sequence-only testing does not capture every relevant variant class.
- name: MRI total kidney volume risk stratification
  description: >-
    Mayo Imaging Classification uses age and height-adjusted total kidney volume to predict
    progression in typical class-1 PKD1/PKD2 ADPKD. It does not establish the diagnosis and
    is not validated for atypical class-2 morphology or minor-gene forms. Prognosis incorporates
    eGFR trajectory and genotype where available.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:40126492
    reference_title: 'Autosomal Dominant Polycystic Kidney Disease: A Review.'
    supports: SUPPORT
    evidence_source: OTHER
    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.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Prognostic information is valid for only class 1 patients with typical imaging ﬁndings
    explanation: KDIGO limits MIC prognostic interpretation to typical morphology.
- name: Risk-based intracranial aneurysm screening
  description: >-
    Discuss screening in people with personal subarachnoid hemorrhage or family intracranial
    aneurysm, subarachnoid hemorrhage or unexplained sudden death who could benefit from treatment.
    Other situations, uncertain family history and patient preferences require shared decisions.
    Noncontrast time-of-flight MRA is preferred; negative high-risk screening may be repeated
    after an individualized 5–10-year interval.
  diagnosis_term:
    preferred_term: Risk-based intracranial aneurysm screening
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:20301424
    reference_title: Polycystic Kidney Disease, Autosomal Dominant.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: MRA examination for intracranial aneurysms in adults determined to be at high risk.
    explanation: GeneReviews supports targeted surveillance; KDIGO 2025 provides current risk and modality details.
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      We recommend screening for ICA in people with ADPKD and a personal history of SAH or a
      positive family history of ICA, SAH, or unexplained sudden death if the person will be
      eligible for treatment and has a reasonable life expectancy.
    explanation: >-
      Current guideline defines the high-risk screening population; other preferences and uncertain
      family history require discussion.
- name: Blood pressure surveillance
  description: >-
    Follow blood pressure throughout the disease course. KDIGO 2025 recommends annual standardized
    office assessment from age five in children and adolescents with or at risk for ADPKD, with
    ambulatory monitoring for selected higher-risk children. This updates the longer interval
    in the 2022 GeneReviews summary.
  diagnosis_term:
    preferred_term: Blood pressure surveillance
    term:
      id: NCIT:C167233
      label: Blood Pressure Measurement
  evidence:
  - reference: url:https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    reference_title: https://kdigo.org/wp-content/uploads/2025/01/KDIGO-2025-ADPKD-Guideline_Executive-Summary.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      BP control in children and adolescents with ADPKD. Standar- dized ofﬁce BP measurement
      should be performed annually in
    explanation: >-
      Annual standardized office BP recommendation; the sentence continues after figure 9 with
      children aged at least five years and adolescents with or at risk for ADPKD.
clinical_trials:
- name: NCT00428948
  phase: PHASE_III
  status: COMPLETED
  description: >-
    TEMPO 3:4 randomized 1445 adults aged 18–50 with enlarged kidneys and preserved creatinine
    clearance for three years. Primary kidney-volume growth was slower with tolvaptan, with
    more aquaretic and hepatic adverse events and discontinuations; trial selection limits generalization.
  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
    reference_title: >-
      A Phase 3, Multi-center, Double-blind, Placebo-controlled, Parallel-arm Trial to Determine
      Long-term Safety and Efficacy of Oral Tolvaptan Tablets Regimens in Adult Subjects With
      Autosomal Dominant Polycystic Kidney Disease
    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.
    evidence_source: OTHER
  - 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.
- name: NCT02160145
  phase: PHASE_III
  status: COMPLETED
  description: >-
    REPRISE randomized 1370 adults after placebo and tolvaptan run-in to one year of tolvaptan
    or placebo in later-stage disease. Entry eGFR and age restrictions and exclusion of run-in
    intolerance limit generalizability. The primary eGFR difference was 1.27 mL/min/1.73 m2;
    dialysis delay was not an observed endpoint.
  evidence:
  - reference: clinicaltrials:NCT02160145
    reference_title: >-
      A Phase 3b, Multi-center, Randomized-withdrawal, Placebo-controlled, Double-blind, Parallel-group
      Trial to Compare the Efficacy and Safety of Tolvaptan (45 to 120 mg/Day, Split-dose) in
      Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal
      Dominant Polycystic Kidney Disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The purpose of the study is to determine whether tolvaptan is effective and safe for the
      treatment of late-stage chronic kidney disease due to autosomal dominant polycystic kidney
      disease (ADPKD)
    explanation: Registry description establishes trial purpose.
  - reference: PMID:29105594
    reference_title: Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 (95%
      confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61
      ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group
    explanation: >-
      REPRISE primary endpoint over one year after a tolerability run-in; 1370 randomized, with
      1331 contributing to the primary analysis. The run-in selected patients able to tolerate
      treatment.
  - reference: url:https://discovery.ucl.ac.uk/10050941/1/nejmoa1710030.pdf
    reference_title: https://discovery.ucl.ac.uk/10050941/1/nejmoa1710030.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      1496 patients entered the single-blind tolvaptan period, of whom 126 withdrew before randomization
    explanation: >-
      Full-text REPRISE results document run-in attrition before randomized follow-up; tolerability
      among randomized participants therefore does not describe every screened or run-in participant.
  target_phenotypes:
  - preferred_term: Decreased glomerular filtration rate
    term:
      id: HP:0012213
      label: Decreased glomerular filtration rate
references:
- reference: PMID:20301424
  title: Polycystic Kidney Disease, Autosomal Dominant.
  tags:
  - GeneReviews
  findings:
  - statement: >-
      Clinical baseline includes age-dependent renal and extrarenal findings, genotype-dependent
      diagnosis and prognosis, complication management and dominant transmission counseling.
- reference: PMID:23892607
  title: Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.
- reference: PMID:27007841
  title: Primary cilia are not calcium-responsive mechanosensors.
- reference: PMID:30042192
  title: Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease.
- reference: PMID:39702469
  title: Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.
- reference: PMID:27077126
  title: Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease.
- reference: PMID:37598857
  title: >-
    Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can
    cause an autosomal dominant form of polycystic kidney disease.
- reference: PMID:39899384
  title: Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.
- reference: PMID:23121377
  title: Tolvaptan in patients with autosomal dominant polycystic kidney disease.
- reference: PMID:29105594
  title: Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.
- reference: PMID:25399733
  title: Blood pressure in early autosomal dominant polycystic kidney disease.
- reference: PMID:39848746
  title: >-
    KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of
    autosomal dominant polycystic kidney disease (ADPKD): executive summary.
datasets:
- accession: metabolomics_workbench:ST000878
  title: Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: METABOLOMICS
  notes: >-
    Mouse kidney metabolomics associated with PMID:27077126. The primary study analyzed 14 male
    kidneys, including eight Pkd1 mutants; bulk metabolite changes often tracked kidney disease
    burden. Its separate paired cell-line experiments found impaired fatty acid oxidation without
    increased glycolysis. This is a mouse tissue dataset, not a patient cohort or evidence of
    a clinically effective diet. The accession was independently resolved against Metabolomics
    Workbench during this review.
notes: >-
  The manual source-curation fallback research report and genuine falcon hypothesis exploration
  were both reviewed. Full GeneReviews and KDIGO 2025 were used with primary cilia, somatic-variant,
  NEK8, metabolic and trial papers. The obligate flow-calcium model is contested. Minor-gene
  phenotypes and historical catalog frequencies should not be generalized to typical PKD1/PKD2
  disease or vice versa. Unresolved mechanisms for incidental extrarenal associations are left
  unconnected rather than inferred from renal-cell evidence. The pituitary adenoma catalog association
  is not an established causal complication. The metabolic mouse dataset motivates investigation,
  not human dietary treatment. No new therapeutic efficacy is asserted for exploratory STING,
  DNA-structure or other hypothesis-report leads.
discussions:
- discussion_id: adpkd_second_hit_universality
  kind: KNOWLEDGE_GAP
  prompt: Which cysts require somatic second hits, and when do those hits occur?
  attaches_to:
  - pathophysiology#Somatic PKD1 or PKD2 inactivation in cyst epithelium
  rationale: >-
    Detection differed between epithelial-enriched samples and smaller whole cysts from end-stage
    kidneys. Variant phase, low-frequency structural variation and early disease remain incompletely
    assessed; neither a universal requirement nor its absence is established.
  status: OPEN
  evidence:
  - reference: PMID:39702469
    reference_title: Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Another major limitation is interpreting data from end-stage kidney, in which it is not
      possible to determine whether a somatic variant was present at cyst initiation or is a
      result of secondary end-stage disease processes.
    explanation: The primary paper states the temporal limitation directly.
- discussion_id: adpkd_metabolic_translation
  kind: KNOWLEDGE_GAP
  prompt: Does correcting fatty acid oxidation improve human ADPKD independently of established cyst burden?
  attaches_to:
  - pathophysiology#Reduced epithelial fatty acid oxidation
  rationale: >-
    The associated mouse dataset and paired cell assays implicate lipid metabolism but do not
    establish a human therapy. Sex, disease burden and model-specific absence of increased glycolysis
    limit generalization.
  status: OPEN
  evidence:
  - reference: PMID:27077126
    reference_title: Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This study also suggests two important new lines for future investigation: how loss of
      Pkd1 results in a cell autonomous fatty acid oxidation defect and, more broadly, how altered
      cellular metabolism leads to dysregulation of tubular diameter and planar cell polarity.
    explanation: Authors identify unresolved upstream and downstream links after the mouse and cell experiments.
differential_diagnoses:
- name: Age-related simple kidney cysts
  description: >-
    A few incidental cysts without family history are not sufficient to diagnose ADPKD. Imaging
    modality, age, cyst distribution and extrarenal findings matter.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: benign simple cysts and other cystic diseases should be considered in the differential diagnosis.
    explanation: >-
      GeneReviews notes this differential when family history is absent; small cysts are frequent
      in otherwise healthy imaged adults.
- name: HNF1B-related kidney disease
  description: >-
    Cystic kidneys can overlap ADPKD, but early diabetes, hypomagnesemia, pancreatic disease
    and congenital urinary-tract anomalies suggest HNF1B-related disease.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Maturity-onset diabetes of the young, pancreatic disease, ↑ liver enzymes, hypomagnesemia,
      congenital kidney & urinary tract anomalies
    explanation: GeneReviews differential table gives distinguishing HNF1B features.
- name: Autosomal recessive polycystic kidney disease
  description: >-
    PKHD1-related recessive disease commonly presents neonatally with enlarged cystic kidneys
    and congenital hepatic fibrosis; severe early ADPKD remains a differential, so onset alone
    is insufficient.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Pulmonary hypoplasia, early-onset kidney failure, liver fibrosis rather than cysts, TKV ↓ over time (rather than ↑)
    explanation: GeneReviews differential table contrasts PKHD1-related ARPKD with typical ADPKD.
- name: Autosomal dominant tubulointerstitial kidney disease
  description: >-
    UMOD, MUC1 and related disorders can include renal cysts, but interstitial fibrosis and
    declining function without marked kidney enlargement predominate. Early gout suggests UMOD/REN
    disease. DNAJB11 and ALG5 phenotypes overlap this distinction.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Fibrosis rather than cysts is the major kidney phenotype.
    explanation: GeneReviews differential table states this discriminator for MUC1/UMOD-related disease.
- name: Tuberous sclerosis complex and PKD1-TSC2 contiguous deletion
  description: >-
    Angiomyolipomas, characteristic skin/brain lesions or cardiac rhabdomyomas suggest tuberous
    sclerosis. A contiguous deletion involving PKD1 and TSC2 can combine severe early cystic
    disease with tuberous sclerosis features.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1246/pdf/Bookshelf_NBK1246.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Kidney angiomyolipomas, skin & brain manifestations, rhabdomyomas, lymphangioleiomyomatosis
    explanation: >-
      GeneReviews differential table lists tuberous sclerosis features and points to the PKD1-TSC2
      contiguous-deletion context.

📚

References & Deep Research

References

PMID:20301424

Polycystic Kidney Disease, Autosomal Dominant.

1 finding

Clinical baseline includes age-dependent renal and extrarenal findings, genotype-dependent diagnosis and prognosis, complication management and dominant transmission counseling.

PMID:23892607

Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease.

No top-level findings curated for this source.

PMID:27007841

Primary cilia are not calcium-responsive mechanosensors.

No top-level findings curated for this source.

PMID:30042192

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

No top-level findings curated for this source.

PMID:39702469

Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.

No top-level findings curated for this source.

PMID:27077126

Fatty Acid Oxidation is Impaired in An Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease.

No top-level findings curated for this source.

PMID:37598857

Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.

No top-level findings curated for this source.

PMID:39899384

Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.

No top-level findings curated for this source.

PMID:23121377

Tolvaptan in patients with autosomal dominant polycystic kidney disease.

No top-level findings curated for this source.

PMID:29105594

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.

No top-level findings curated for this source.

PMID:25399733

Blood pressure in early autosomal dominant polycystic kidney disease.

No top-level findings curated for this source.

PMID:39848746

KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD): executive summary.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

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.

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References & Deep Research

References

Deep Research

Autosomal Dominant Polycystic Kidney Disease Deep Research Fallback

Provider Attempts

Evidence Scope Used For Curation

Curation Conclusions