Familial Vesicoureteral Reflux

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Mappings

MONDO

MONDO:0017329 familial vesicoureteral reflux

MONDO:0017329 (familial vesicoureteral reflux) is the disease term for this entry; the entry scope (primary, non-syndromic, familial VUR including the VUR1-VUR8 series and the X-linked form) matches the MONDO/Orphanet definition.

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Inheritance

3

Autosomal dominant with incomplete penetrance HP:0000006

Many multigenerational VUR kindreds segregate the trait in a pattern consistent with autosomal dominant inheritance with reduced penetrance and highly variable expressivity (grade, laterality, and presence of reflux nephropathy all vary within a pedigree). Dominant-model parametric linkage underpins the VUR1 (1p13) and 10q26 signals. A 2q37 dominant locus is also reported in the linkage literature but has no OMIM VUR series number and is not modelled as a subtype here.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (3 references)

PMID:19443636 SUPPORT Human Clinical

"Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance."

States that the mapped primary-VUR loci (1p13 and 2q37) were identified under an autosomal dominant model. Note this is the background framing of prior scans, not a result of this paper, whose own dominant-model analysis was negative.

PMID:29097723 SUPPORT Human Clinical

"parametric linkage analysis of 460 families (1062 affected individuals) under a dominant model identified a single region, on 10q26, that showed strong linkage (HLOD = 4.90; ZLRLOD = 4.39) to VUR"

The largest VUR linkage study to date obtained its only significant signal under a dominant model, supporting dominant transmission in a subset of families.

PMID:1623385 SUPPORT Human Clinical

"Genetic analysis suggests that most instances of familial vesicoureteric reflux arise secondary to expression of autosomal dominant single genes with incomplete penetrance."

Direct support for the structured penetrance qualifier: segregation analysis of a sibship in which reflux skipped the preceding and succeeding generations concluded that dominant alleles with incomplete penetrance explain most familial VUR.

Autosomal recessive (VUR7 kindreds) HP:0000007

Absence of reflux in the parents of many affected children prompted testing of a recessive model, which uncovered the chromosome 12p11-q13 (VUR7) locus across pedigrees of several ancestries.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:19443636 SUPPORT Human Clinical

"In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping."

Directly documents recessive inheritance of a major primary-VUR locus.

Polygenic and multifactorial contribution HP:0010982

In most families no single Mendelian locus is identified; sib-pair and genome-wide association analyses point to multiple contributing loci of small effect superimposed on the familial clustering.

Polygenic inheritance

Show evidence (2 references)

PMID:19959718 SUPPORT Human Clinical

"The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations."

A large linkage/association scan failed to find major loci, favouring an oligogenic/polygenic architecture in most families.

PMID:19690587 SUPPORT Human Clinical

"These results suggested that multiple genes are likely to contribute to the formation of VUR phenotype."

Affected sib-pair analysis identified three independent linkage peaks, supporting a multigenic contribution.

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Subtypes

9

Vesicoureteral reflux 1 (VUR1, 1p13 locus) MONDO:0008653

The first mapped familial VUR locus, on chromosome 1p13, defined by the original genome-wide search in seven European families with apparently dominant inheritance of VUR and reflux nephropathy. The causal gene has not been identified. OMIM 193000 is the index entry of the VUR phenotypic series.

Show evidence (2 references)

PMID:10739767 SUPPORT Human Clinical

"The most positive locus spanned 20 cM on 1p13 between GATA176C01 and D1S1653 and had a nonparametric LOD score (NPL) of 5.76 (P=.0002) and a parametric LOD score of 3.16."

Defines the VUR1 locus interval on 1p13 with genome-wide significant linkage.

PMID:19959718 REFUTE Human Clinical

"We found modest evidence of linkage but no clear overlap with previous studies."

Counter-evidence: a much larger whole-genome scan did not replicate the earlier VUR linkage peaks, so VUR1 (and by the same argument the sib-pair-derived VUR4/VUR5/VUR6 loci) should be read as unreplicated mapping results, not as established disease loci.

Vesicoureteral reflux 2 (VUR2, ROBO2) MONDO:0012573

about 3% of familial primary VUR families ROBO2 hgnc:10250 Autosomal dominant inheritance

VUR caused by disruption of ROBO2 (3p12.3), the receptor for SLIT ligands. Identified through a de novo t(Y;3) translocation disrupting ROBO2 in a man with severe bilateral VUR and ureterovesical junction defects, with segregating intracellular missense variants in two further CAKUT/VUR families. Rare ROBO2 variants account for roughly 3% of familial primary VUR families in the largest sequenced cohort.

Show evidence (1 reference)

PMID:17357069 SUPPORT Human Clinical

"This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro."

Establishes ROBO2 disruption as the lesion underlying this VUR subtype.

Vesicoureteral reflux 3 (VUR3, SOX17) MONDO:0013356

SOX17 hgnc:18122

VUR associated with mutation of SOX17 (8q11.23), an HMG-box transcription factor and Wnt/beta-catenin antagonist. The recurrent p.Y259N allele accumulates as protein and produces excessive inhibition of Wnt signalling during kidney and urinary tract development.

Show evidence (1 reference)

PMID:20960469 SUPPORT Human Clinical

"We have identified mutations in SOX17, an HMG-box transcription factor and Wnt signaling antagonist, in eight patients with CAKUT (seven vesico-ureteric reflux, one pelvic obstruction)."

Documents SOX17 mutation in patients whose predominant CAKUT phenotype is vesicoureteric reflux.

Vesicoureteral reflux 4 (VUR4, chromosome 5 locus) MONDO:0013682

Susceptibility locus on chromosome 5 identified by affected sib-pair analysis of 98 multiplex familial VUR families; the strongest of three peaks in that scan (LOD > 4). No causal gene has been identified.

Show evidence (1 reference)

PMID:19690587 SUPPORT Human Clinical

"we identified a genome-wide statistically significant linkage peak with an LOD score greater than 4 on chromosome 5 and two linkage peaks with LOD scores greater than 3.6 on chromosomes 13 and 18 were identified in these 98 families"

Defines the chromosome 5 locus that OMIM designates VUR4.

Vesicoureteral reflux 5 (VUR5, chromosome 13 locus) MONDO:0013683

Susceptibility locus on chromosome 13 from the same affected sib-pair scan (LOD > 3.6). No causal gene has been identified.

Show evidence (1 reference)

PMID:19690587 SUPPORT Human Clinical

"two linkage peaks with LOD scores greater than 3.6 on chromosomes 13 and 18 were identified in these 98 families"

Defines the chromosome 13 locus that OMIM designates VUR5.

Vesicoureteral reflux 6 (VUR6, chromosome 18 locus) MONDO:0013684

Susceptibility locus on chromosome 18 from the same affected sib-pair scan (LOD > 3.6). No causal gene has been identified.

Show evidence (1 reference)

PMID:19690587 SUPPORT Human Clinical

"two linkage peaks with LOD scores greater than 3.6 on chromosomes 13 and 18 were identified in these 98 families"

Defines the chromosome 18 locus that OMIM designates VUR6.

Vesicoureteral reflux 7 (VUR7, 12p11-q13, recessive) MONDO:0014161

Autosomal recessive inheritance

Recessively inherited primary VUR mapping to chromosome 12p11-q13. Unlike the other loci, it emerged only when a recessive model was tested, and it contributed across pedigrees of several ancestries, suggesting a relatively common recessive risk allele.

Show evidence (1 reference)

PMID:19443636 SUPPORT Human Clinical

"The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations."

Defines the recessive VUR7 locus and its cross-population contribution.

Vesicoureteral reflux 8 (VUR8, TNXB) MONDO:0014422

about 9% of familial primary VUR families TNXB hgnc:11976 Autosomal dominant inheritance

VUR caused by heterozygous missense variants in TNXB (tenascin XB, 6p21.3), an extracellular matrix glycoprotein expressed in the developing ureterovesical junction. Affected individuals frequently also have joint hypermobility, reflecting the connective-tissue role of tenascin X. TNXB carriers in a Chinese registry had a higher hazard of progression to kidney failure, although that estimate rests on only three carriers and the confidence interval is correspondingly wide (HR 20.3, 95% CI 2.4-168.7). TNXB is the most common identified cause of autosomal dominant familial primary VUR, found in about 9% of families in the largest sequenced cohort.

Show evidence (2 references)

PMID:23620400 SUPPORT Human Clinical

"We obtained a significant multipoint parametric logarithm of odds score of 3.3 on chromosome 6p, and whole-exome sequencing identified a deleterious heterozygous mutation (T3257I) in the gene encoding tenascin XB (TNXB in 6p21.3)."

Establishes TNXB as the VUR8 gene by linkage plus exome sequencing in a hereditary VUR family.

PMID:26408188 SUPPORT Human Clinical

"all the individuals with the TNXB variants who had joint mobility examination done have significant joint hypermobility as assessed by Beighton score"

Documents the connective-tissue (joint hypermobility) feature that accompanies TNXB-related familial VUR.

Vesicoureteral reflux, X-linked (VURX) MONDO:0010755

X-linked inheritance

A rare X-linked form of familial vesicoureteral reflux recognised as a distinct OMIM entry (314550) outside the autosomal VUR1-VUR8 series, based on isolated pedigrees in which only male relatives connected through unaffected females are affected. No causal gene has been identified, and the overall evidence for X linkage in VUR is weak: male-to-male transmission and the female predominance of VUR argue against it, so this subtype is retained for completeness of the nosology rather than as an established molecular entity.

Show evidence (2 references)

PMID:1142496 SUPPORT Human Clinical

"This pedigree strongly suggests and X-linked mode of genetic transmission."

Original description of an apparently X-linked familial VUR pedigree (quoted verbatim, including the typographical error in the abstract).

PMID:21981614 REFUTE Human Clinical

"On the other hand male-to-male transmission and a higher ratio of females to males argued against X-linked inheritance."

Counter-evidence: the epidemiology of familial VUR as a whole is inconsistent with X-linked inheritance, so VURX remains a contested, pedigree-level designation.

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Discussions and Knowledge Gaps

3

What genes underlie the VUR1 (1p13), VUR4 (chromosome 5), VUR5 (chromosome 13), VUR6 (chromosome 18), VUR7 (12p11-q13) and 10q26 linkage intervals?

KNOWLEDGE GAP OPEN vur_unidentified_locus_genes

Attached to

pathophysiology#Abnormal Ureteric Bud Outgrowth Position

Six of the mapped familial VUR loci still have no identified gene, and even resequencing of the strongest interval (10q26, ~9 Mb, 69 genes) did not clearly implicate a single gene. Together with the roughly 7% monogenic diagnostic yield of exome sequencing in unselected primary VUR and the finding that more than 80% of familial cases have no identifiable variant, this means the molecular basis of most familial VUR is unknown. Whether the missing signal is non-coding regulatory variation acting on ureteric bud positioning, structural variation, or oligogenic combinations is unresolved.

Proposed experiments

Whole-genome sequencing of large multiplex VUR pedigrees

vur_wgs_multiplex_pedigrees

Sequence whole genomes (not exomes) in multigenerational familial VUR kindreds linked to the mapped intervals, to capture non-coding regulatory and structural variation missed by exome sequencing.

Single-cell and spatial atlas of the developing human ureterovesical junction

vur_uvj_single_cell_atlas

Profile the human nephric duct and forming ureterovesical junction by single-cell and spatial transcriptomics to prioritise candidate genes expressed at the budding site within each linkage interval.

Show evidence (1 reference)

PMID:29097723 SUPPORT Human Clinical

"The ~9Mb region contains 69 genes, including some good biological candidates. Resequencing this region in selected individuals did not clearly implicate any gene but FOXI2, FANK1 and GLRX3 remain candidates for further investigation."

Documents the unresolved state of even the strongest familial VUR linkage interval.

Can any intervention prevent the renal lesion of familial VUR, given that halving urinary tract infection does not reduce renal scarring?

KNOWLEDGE GAP OPEN vur_congenital_vs_acquired_renal_lesion

Attached to

pathophysiology#Renal Cortical Scarring pathophysiology#Congenital Renal Hypodysplasia

RIVUR showed that continuous antimicrobial prophylaxis halves recurrent UTI without changing the rate of renal scarring, while carrying a clear resistance cost. If a substantial fraction of the renal lesion is congenital hypodysplasia determined at the time of ureteric bud outgrowth, then no postnatal infection-directed strategy can prevent it, and the appropriate outcome measure for VUR trials may need to change. The relative contribution of congenital versus acquired injury in an individual child cannot currently be determined at diagnosis.

Proposed experiments

Neonatal DMSA cohort partitioning congenital from acquired renal lesions

vur_neonatal_dmsa_partition

Prospectively image children detected antenatally or at first UTI with early (neonatal) DMSA plus longitudinal follow-up imaging, to separate pre-existing hypodysplasia from newly acquired post-pyelonephritic scars.

Genotype-stratified analysis of prophylaxis outcomes

vur_genotype_stratified_prophylaxis

Re-analyse or prospectively stratify prophylaxis trials by molecular subtype (e.g. TNXB and PAX2 carriers) to test whether genotype predicts response to infection-directed therapy.

Show evidence (2 references)

PMID:24795142 SUPPORT Human Clinical

"The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively)."

The negative scarring outcome that motivates the gap.

PMID:16433689 SUPPORT Other

"Despite treatment of affected children for the past 40 years, the incidence of end-stage renal disease secondary to VUR has not decreased."

Forty years of infection-directed treatment has not changed the population-level renal outcome.

Does pharmacological MEK/ERK inhibition during ureteric bud outgrowth, which prevents CAKUT in Robo2/Gen1 double-heterozygous mice, have any bearing on human familial VUR?

HUMAN MODEL MISMATCH OPEN vur_mek_inhibition_model_mismatch

Attached to

pathophysiology#Abnormal Ureteric Bud Outgrowth Position

Intraperitoneal U0126 given to pregnant mice prevents the CAKUT phenotype in Robo2(PB/+)Gen1(PB/+) offspring, identifying MAPK/ERK as a convergent downstream node of the budding-position defect. This is a striking mechanistic result, but its translational validity is unknown: the mouse model is engineered and digenic, the intervention is a systemic MEK inhibitor given during pregnancy (with obvious developmental-toxicity and ethical barriers), and no human VUR has been shown to be MAPK/ERK-driven. It is a mechanistic probe of the budding-position model rather than a therapeutic lead.

Proposed experiments

ERK pathway activity in human ROBO2/SLIT2 variant carriers

vur_erk_patient_cells

Test whether patient-derived fibroblasts or urinary-tract organoids from human ROBO2 or SLIT2 variant carriers show altered ERK phosphorylation comparable to the mouse model.

Oligogenic burden test for GEN1 and ERK-pathway modifiers

vur_gen1_oligogenic_burden

Determine whether GEN1 or other ERK-pathway modifier alleles contribute to human familial VUR in oligogenic burden analyses of multiplex cohorts.

Show evidence (1 reference)

PMID:36870240 SUPPORT Model Organism

"Intraperitoneal injection of U0126 during pregnancy prevented the development of the CAKUT phenotype in Robo2PB/+Gen1PB/+ mice."

The model-system result whose translation to human familial VUR is unestablished.

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Pathophysiology

12

SLIT2-ROBO2 Signaling Loss

Loss or dominant-negative disruption of the ROBO2 receptor abolishes repulsive SLIT2-ROBO2 signalling at the caudal nephric duct. In the intact system this signal restricts the field in which GDNF can induce a bud, so its loss permits ectopic and supernumerary ureteric bud outgrowth. This is the proximal molecular lesion of VUR2.

ROBO2 hgnc:10250 SLIT2 hgnc:11086

Roundabout signaling pathway GO:0035385 ↓ DECREASED

transmembrane signaling receptor activity GO:0004888 ↓ DECREASED

Downstream

Abnormal Ureteric Bud Outgrowth Position

Show evidence (1 reference)

PMID:17357069 SUPPORT In Vitro

"This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro."

Functional demonstration that the patient ROBO2 alleles abolish SLIT-ROBO signalling, defining the molecular lesion.

SOX17 Gain of Wnt Antagonism

The recurrent SOX17 p.Y259N allele is not a null: the mutant protein accumulates several-fold above wild type and, being a Wnt/beta-catenin antagonist, delivers a correspondingly excessive brake on canonical Wnt signalling during kidney and urinary tract development. This is the proximal molecular lesion of VUR3.

SOX17 hgnc:18122

negative regulation of canonical Wnt signaling pathway GO:0090090 ↑ INCREASED

DNA-binding transcription factor activity GO:0003700 ⚠ ABNORMAL

Downstream

Abnormal Ureteric Bud Outgrowth Position

Show evidence (1 reference)

PMID:20960469 SUPPORT In Vitro

"Transfection studies indicated a 5-10-fold increase in the levels of the mutant protein relative to wild-type SOX17 in transfected kidney cells."

Shows the mutant protein accumulates rather than being lost, the basis for an excess-antagonism (not loss-of-function) mechanism.

Tenascin-X Focal Adhesion Defect

Missense variants in the fibronectin type III region of tenascin XB impair the cell-matrix coupling that TNXB normally supports. Patient fibroblasts show reduced motility and reduced focal adhesion kinase phosphorylation, consistent with defective disassembly of focal adhesions. This is the proximal molecular lesion of VUR8 and acts on the ureterovesical junction directly rather than through bud positioning.

TNXB hgnc:11976

cell-matrix adhesion GO:0007160 ⚠ ABNORMAL

extracellular matrix structural constituent GO:0005201 ⚠ ABNORMAL

Downstream

Ureterovesical Junction Incompetence

Show evidence (1 reference)

PMID:23620400 SUPPORT In Vitro

"Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix."

Patient-derived cells define the molecular consequence of the TNXB allele.

Abnormal Ureteric Bud Outgrowth Position

Primary VUR originates during the fifth week of human development, when the ureteric bud sprouts from the caudal nephric (Wolffian) duct. Genetic perturbation of the signals that fix the budding site — SLIT2-ROBO2 repulsive guidance, GDNF/RET, and Wnt/beta-catenin (antagonised by SOX17) — shifts the bud cranially or laterally, or produces ectopic/duplicated buds. Because the bud stalk becomes the ureter and its insertion becomes the ureteric orifice, a misplaced bud lands laterally on the developing trigone with a short intramural course. The same misplacement means the bud contacts an inappropriate region of metanephric mesenchyme, so intrinsic renal hypodysplasia is generated at the same time as the refluxing ureter — the unified "budding position" explanation for why VUR and congenital renal malformation co-segregate.

ureteric bud cell CL:4030066

ROBO2 hgnc:10250 SLIT2 hgnc:11086 SOX17 hgnc:18122

ureteric bud formation GO:0060676 ⚠ ABNORMAL mesonephric duct development GO:0072177 ⚠ ABNORMAL Roundabout (SLIT-ROBO) signaling pathway GO:0035385 ↓ DECREASED negative regulation of canonical Wnt signaling pathway GO:0090090 ↑ INCREASED

ureter UBERON:0000056

Downstream

Ureterovesical Junction Incompetence

Congenital Renal Hypodysplasia

Show evidence (4 references)

PMID:16433689 SUPPORT Other

"Some of the gene candidates that have been identified regulate the position of ureteric budding, a critical step in both kidney and urinary tract development."

States the core developmental model — VUR genes act on ureteric bud positioning. Evidence source is OTHER because this is a review synthesising human and mouse data.

PMID:16433689 SUPPORT Other

"Vesicoureteric reflux (VUR) is a congenital urinary tract defect caused by the failure of the ureter to insert correctly into the bladder."

Frames VUR as a defect of ureteric insertion rather than an acquired bladder problem.

PMID:17357069 SUPPORT Model Organism

"Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes."

Mouse Robo2 dosage reduction reproduces the human CAKUT-VUR phenotype, supporting SLIT-ROBO control of bud position.

+ 1 more reference

Ureterovesical Junction Incompetence

The ureterovesical junction normally acts as a passive flap valve: the distal ureter runs obliquely for 1-2 cm within the bladder wall between the mucosa and the detrusor, so rising intravesical pressure compresses the tunnel shut. In primary VUR the intramural tunnel is too short relative to ureteric diameter and the orifice is laterally displaced, so the valve fails and urine refluxes during filling and, above all, during voiding. Extracellular-matrix competence of the junction also matters: TNXB, mutated in VUR8, is expressed in the uroepithelium of the ureterovesical junction at the time it forms and is proposed to generate the tensile forces that close it, with patient fibroblasts showing defective focal-adhesion turnover.

ureter urothelial cell CL:1000706 ureter smooth muscle cell CL:1000979

TNXB hgnc:11976

ureter maturation GO:0035799 ⚠ ABNORMAL cell-matrix adhesion GO:0007160 ⚠ ABNORMAL

ureterovesical junction UBERON:0009973 trigone of urinary bladder UBERON:0001257

Downstream

Retrograde Urine Flow and Intrarenal Reflux

Show evidence (4 references)

PMID:33085409 SUPPORT Other

"Vesicoureteral reflux (VUR) is the retrograde urine flow from the urinary bladder to the upper urinary tract, usually during voiding. A short intramural ureter often causes this abnormal backward flow of urine."

Identifies the short intramural ureter as the proximate anatomical cause of reflux. Evidence source is OTHER because this is a clinical reference review.

PMID:23620400 SUPPORT Human Clinical

"Immunohistochemical studies revealed that the human uroepithelial lining of the ureterovesical junction expresses TNXB, suggesting that TNXB may be important for generating tensile forces that close the ureterovesical junction during voiding."

Provides the molecular link between a familial VUR gene and closure of the ureterovesical junction.

PMID:23620400 SUPPORT In Vitro

"Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix."

Patient-derived cells show the cell-matrix adhesion defect proposed to underlie junction incompetence.

+ 1 more reference

Congenital Renal Hypodysplasia

A component of the renal lesion in familial VUR is present at birth and is independent of infection: because the misplaced ureteric bud induces an inappropriate region of metanephric mesenchyme, the kidney it induces is hypoplastic and/or dysplastic. This "congenital reflux nephropathy" is not preventable by antibiotic prophylaxis or anti-reflux surgery, and accounts for a substantial share of the chronic kidney disease attributed to VUR.

metanephros development GO:0001656 ⚠ ABNORMAL

kidney UBERON:0002113

Downstream

Reflux Nephropathy and Progressive Nephron Loss

Show evidence (2 references)

PMID:16433689 SUPPORT Other

"Analysis of data from humans and mice suggests that some of the renal damage associated with VUR is congenital and is due to a kidney malformation."

Establishes the congenital (malformation) component of renal damage, distinct from acquired scarring.

PMID:29097723 SUPPORT Human Clinical

"Despite treatment improvements, associated renal lesions - congenital dysplasia, acquired scarring or both - are a common cause of childhood hypertension and renal failure."

Confirms that both a congenital dysplastic and an acquired scarring lesion contribute to the renal outcome.

Retrograde Urine Flow and Intrarenal Reflux

Once the flap valve fails, urine flows retrogradely up the ureter during voiding. In higher grades the refluxed bolus reaches the renal pelvis and then enters the collecting ducts (intrarenal reflux) through gaping duct orifices on compound papillae, which are concentrated at the upper and lower renal poles. Intrarenal reflux is the step that converts a ureteric problem into a parenchymal one, and it defines the polar distribution of the scars that follow. Grade (I-V, International Reflux Study) tracks the extent of retrograde filling and dilation and is the main determinant of both spontaneous resolution and scarring risk.

renal pelvis UBERON:0001224 ureter UBERON:0000056

Downstream

Ascending Infection and Acute Pyelonephritis

Reflux Nephropathy and Progressive Nephron Loss

Show evidence (2 references)

PMID:3153345 SUPPORT Other

"Primarily, only gaping collecting duct orifices, confined to compound papillae and mainly situated at the kidney poles, allow intrarenal reflux."

Defines the anatomical route of intrarenal reflux and its polar distribution.

PMID:33085409 SUPPORT Other

"Grades III to V are considered dilating or high-grade VUR and are associated with an increased risk of UTIs and renal scarring, especially grades IV and V."

Links the degree of retrograde filling/dilation to downstream renal risk.

Ascending Infection and Acute Pyelonephritis

Reflux carries bladder urine — and any bacteria in it — into the renal pelvis and, via intrarenal reflux, into the parenchyma, converting cystitis into acute pyelonephritis. Segmental scars form only in segments that both receive intrarenal reflux and are exposed to bacterial infection, making infection the essential second hit for the acquired component of reflux nephropathy. Bladder and bowel dysfunction (detrusor overactivity, voiding postponement, constipation) markedly increases infection risk on top of the reflux itself. This node is the kidney-specific instance of the fibrotic module's dysregulated wound-healing trigger.

kidney epithelial cell CL:0002518

response to bacterium GO:0009617 ↑ INCREASED wound healing GO:0042060 ↕ DYSREGULATED

cortex of kidney UBERON:0001225

Downstream

Renal Inflammatory Cell Recruitment

Show evidence (3 references)

PMID:3153345 SUPPORT Other

"These scars are confined to segments with intrarenal reflux which are, in addition, exposed to bacterial infection."

Establishes infection plus intrarenal reflux as the joint requirement for the acquired scar.

PMID:33085409 SUPPORT Other

"Patients with VUR with bladder or bowel dysfunction are at a higher risk of developing infections despite continuous prophylaxis and have a much lower rate of spontaneous resolution (31% compared to 61%) and reduced success rates after endoscopic VUR surgical procedures."

Quantifies bladder-bowel dysfunction as a modifier of infection risk and of resolution.

PMID:27760770 SUPPORT Model Organism

"Transurethral inoculation of uropathogenic Escherichia coli in C3H/HeOuJ mice leads to renal mucosal injury, tubulointerstitial nephritis, and cortical fibrosis."

In an immunocompetent mouse model that itself has vesicoureteral reflux, ascending uropathogenic E. coli infection produces exactly this injury step, establishing it as the tissue-injury trigger of the fibrotic cascade.

Renal Inflammatory Cell Recruitment

Bacterial burden in the refluxing renal segment recruits neutrophils and monocyte-derived macrophages in proportion to that burden. Neutrophils control bacterial ascent, but the macrophage-dominated inflammatory response is strong and ineffective, and it is the extent of this inflammation — not the infection itself — that best predicts subsequent fibrosis. Experimental tipping of the neutrophil-macrophage balance towards macrophages worsens scarring, identifying this recruitment step as the amplifier that converts a treatable infection into permanent renal damage.

neutrophil CL:0000775 monocyte-derived macrophage CL:0000235

inflammatory response GO:0006954 ↑ INCREASED leukocyte migration GO:0050900 ↑ INCREASED

cortex of kidney UBERON:0001225

Downstream

Interstitial Myofibroblast Activation

Show evidence (2 references)

PMID:27760770 SUPPORT Model Organism

"The extent of fibrosis correlates most significantly with inflammation at 7 and 28 days postinfection. The recruitment of neutrophils and inflammatory macrophages to infected kidneys is proportional to renal bacterial burden."

Directly ties leukocyte recruitment to the magnitude of subsequent renal fibrosis in a refluxing mouse model.

PMID:33148615 SUPPORT Model Organism

"Exacerbated macrophage-mediated inflammatory responses promoted renal scarring and compromised renal function, as indicated by elevated serum creatinine, BUN, and potassium."

Establishes the macrophage arm of the recruitment response as causal for scarring rather than merely correlated with it.

Interstitial Myofibroblast Activation

Macrophage-derived pro-fibrotic cytokines, principally TGF-beta, drive resident interstitial fibroblasts to transdifferentiate into alpha-smooth-muscle-actin-positive myofibroblasts, the effector cell of renal interstitial fibrosis. Human genetic data support a causal role for this axis specifically in post-UTI renal scarring: an activating TGF-beta1 promoter allele predicts scar formation after childhood pyelonephritis independently of whether reflux is present.

fibroblast CL:0000057 myofibroblast CL:0000186

transforming growth factor beta receptor signaling pathway GO:0007179 ↑ INCREASED

cortex of kidney UBERON:0001225

Downstream

Renal Cortical Scarring

Show evidence (2 references)

PMID:19861314 SUPPORT Human Clinical

"The -509 T allele in the TGFbeta-1 promoter was significantly more common in cases with renal scarring (51%) than in non-scarring patients (22.4%) and controls (23.6%) (both P < 0.0001)."

Human genetic evidence that TGF-beta1 activity is causally upstream of post-UTI renal scarring, supporting the TGF-beta-driven mesenchymal activation step in this disease rather than only in fibrosis generally.

PMID:19861314 SUPPORT Human Clinical

"Multiple logistic regression testing identified the presence of VUR (odds ratio 12.4, CI 3.8-40; P < 0.001) and the TGFbeta-1 -509 T allele (OR 6.1, CI 2.4-15.5; P < 0.001) as independent risk factors for renal scarring after UTI."

Places reflux and the TGF-beta1 activating allele as independent, multiplicative risk factors for the scarring endpoint.

Renal Cortical Scarring

Activated interstitial myofibroblasts deposit excess collagen while matrix degradation lags, producing a wedge-shaped, polar cortical scar with tubulointerstitial fibrosis and overlying calyceal clubbing. Scar contraction can itself convert closed collecting-duct orifices into gaping ones, enlarging the area at risk and creating a self-amplifying loop; new scars continue to appear beyond 5 years of age.

myofibroblast CL:0000186 macrophage CL:0000235

extracellular matrix organization GO:0030198 ↑ INCREASED collagen fibril organization GO:0030199 ↑ INCREASED collagen biosynthetic process GO:0032964 ↑ INCREASED

cortex of kidney UBERON:0001225

Downstream

Reflux Nephropathy and Progressive Nephron Loss

Retrograde Urine Flow and Intrarenal Reflux

Show evidence (4 references)

PMID:27760770 SUPPORT Model Organism

"This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis."

Anchors the cortical-fibrosis endpoint of this node in a model validated against human acquired renal scarring.

PMID:3153345 SUPPORT Other

"Scar contraction and obstruction seem to be able to transform closed collecting duct orifices into gaping ones, thereby enlarging the parenchymal area prone to intrarenal reflux and to renal scarring."

Documents the self-amplifying loop between scarring and further intrarenal reflux.

PMID:3153345 SUPPORT Other

"There is a greater tendency for scarring to develop with more severe VUR, but new renal scars can develop with all grades of VUR."

Grades the scarring risk and shows it is not confined to high-grade reflux. Evidence source is OTHER because Olbing 1987 is a narrative review of clinical and experimental data rather than a primary cohort report.

+ 1 more reference

Reflux Nephropathy and Progressive Nephron Loss

The combined congenital (hypodysplastic) and acquired (post-pyelonephritic scarring) lesions reduce functioning nephron mass. Reflux nephropathy is a leading cause of childhood hypertension and contributes roughly 10-15% of kidney failure requiring dialysis or transplantation in children and young adults.

kidney UBERON:0002113

Show evidence (3 references)

PMID:19959718 SUPPORT Human Clinical

"Primary vesicoureteric reflux accounts for approximately 10% of kidney failure requiring dialysis or transplantation, and sibling studies suggest a large genetic component."

Quantifies the contribution of primary VUR to kidney failure.

PMID:17357069 SUPPORT Human Clinical

"VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults."

Independent estimate of the share of ESRD attributable to reflux nephropathy.

PMID:34059960 SUPPORT Human Clinical

"Eighty-eight patient (23.2%) exhibited impaired renal function at their last visit, and 18 of them (20.5%) developed ESRD at the median age of 7.0 (IQR 0.9-11.4) years."

Registry data on the frequency and timing of kidney failure in primary VUR.

⬡

Pathograph

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

●

Phenotypes

16

Cardiovascular 1

Hypertension HP:0000822

Show evidence (1 reference)

PMID:29097723 SUPPORT Human Clinical

"associated renal lesions - congenital dysplasia, acquired scarring or both - are a common cause of childhood hypertension and renal failure"

Links the renal lesions of VUR to childhood hypertension.

Genitourinary 3

Reflux Nephropathy FREQUENT HP:0000112

Show evidence (1 reference)

PMID:21441121 SUPPORT Human Clinical

"RN was radiologically proven in 223 patients."

Radiologically proven reflux nephropathy in 223 of the 407 patients (55%) in a UK familial-VUR sibling-pair cohort, supporting the FREQUENT band. Note that this cohort was ascertained through tertiary paediatric nephrology centres and is therefore enriched for nephropathy.

Chronic Kidney Disease OCCASIONAL HP:0012622

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:34059960 SUPPORT Human Clinical

"Eighty-eight patient (23.2%) exhibited impaired renal function at their last visit, and 18 of them (20.5%) developed ESRD at the median age of 7.0 (IQR 0.9-11.4) years."

Registry data: 23.2% of 379 children with primary VUR had impaired renal function at last visit.

Stage 5 Chronic Kidney Disease VERY_RARE HP:0003774

Show evidence (2 references)

PMID:33085409 SUPPORT Other

"End-stage renal failure in children due to reflux nephropathy accounts for about 5% of all pediatric renal transplants."

Establishes the population-level contribution of reflux nephropathy to paediatric kidney failure. This is a population-attributable fraction over a transplant denominator and does not by itself give a per-patient risk; the frequency band is set from the cohort denominator in the next evidence item.

PMID:34059960 SUPPORT Human Clinical

"Eighty-eight patient (23.2%) exhibited impaired renal function at their last visit, and 18 of them (20.5%) developed ESRD at the median age of 7.0 (IQR 0.9-11.4) years."

Derived-count basis for the VERY_RARE band: 18 of the 379 recruited children with primary VUR reached ESRD, i.e. 4.7% of the whole cohort.

Musculoskeletal 1

Joint Hypermobility HP:0001382

Show evidence (1 reference)

PMID:26408188 SUPPORT Human Clinical

"all the individuals with the TNXB variants who had joint mobility examination done have significant joint hypermobility as assessed by Beighton score"

Documents joint hypermobility in TNXB-variant carriers with primary VUR.

Other 11

Primary Vesicoureteral Reflux OBLIGATE HP:0033738

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"Vesicoureteral reflux (VUR) is the retrograde urine flow from the urinary bladder to the upper urinary tract, usually during voiding."

Defines the cardinal phenotype.

High-Grade (Dilating) Vesicoureteral Reflux High-grade vesicoureteral reflux HP:0033734

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"Grades III to V are considered dilating or high-grade VUR and are associated with an increased risk of UTIs and renal scarring, especially grades IV and V."

Defines dilating grades and their risk profile. Frequency is deliberately omitted because grade distribution varies markedly with ascertainment (antenatal vs. post-UTI vs. sibling screening).

Intrarenal Reflux HP:0033742

Show evidence (1 reference)

PMID:3153345 SUPPORT Other

"Primarily, only gaping collecting duct orifices, confined to compound papillae and mainly situated at the kidney poles, allow intrarenal reflux."

Documents intrarenal reflux and its anatomical basis.

Recurrent Urinary Tract Infections FREQUENT HP:0000010

Show evidence (1 reference)

PMID:21441121 SUPPORT Human Clinical

"Clinical presentation was established in 122; 92 had urinary tract infections and 16 had abnormal antenatal renal scans."

Derived-count basis for the FREQUENT band, with both denominators stated: 92 of the 122 patients whose mode of presentation was recorded (75%) presented with urinary tract infection, which is 92/407 (23%) of the full sibling-pair cohort. Presentation with UTI is not identical to the "recurrent" qualifier of HP:0000010, so the band is supported as an estimate of symptomatic urinary infection burden rather than as a direct count of recurrence.

Acute Pyelonephritis Recurrent pyelonephritis HP:0012787

Temporal: RECURRENT

Show evidence (1 reference)

PMID:3153345 SUPPORT Other

"The frequency of acute pyelonephritic attacks decreased significantly after operation."

Documents acute pyelonephritis as a recurring event in VUR and its reduction after anti-reflux surgery.

Renal Cortical Scarring OCCASIONAL Renal cortical atrophy HP:0002048

Show evidence (1 reference)

PMID:24795142 SUPPORT Human Clinical

"The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively)."

In the RIVUR randomised trial, renal scarring occurred in roughly 10-12% of children with VUR over 2 years, supporting the OCCASIONAL band.

Renal Hypoplasia and Dysplasia Renal hypoplasia/aplasia HP:0008678

Show evidence (1 reference)

PMID:29097723 SUPPORT Human Clinical

"Despite treatment improvements, associated renal lesions - congenital dysplasia, acquired scarring or both - are a common cause of childhood hypertension and renal failure."

Documents congenital dysplasia as a component renal lesion.

Renal Dysplasia HP:0000110

Show evidence (1 reference)

PMID:16433689 SUPPORT Other

"Analysis of data from humans and mice suggests that some of the renal damage associated with VUR is congenital and is due to a kidney malformation."

Supports a congenital maldevelopment (dysplastic) component of the renal lesion in VUR, as opposed to purely acquired scarring.

Hydronephrosis HP:0000126

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"A systematic review of 34 studies indicated that approximately 16% of neonates with ultrasound evidence of hydronephrosis eventually have VUR."

Links antenatal hydronephrosis to the detection of VUR.

Duplicated Collecting System HP:0000081

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"Negative predictive factors for spontaneous resolution of VUR include female gender, higher grade reflux (grades IV and V), other ureteral abnormalities, complete renal duplication, periureteral diverticula, bladder or bowel disorders, and renal pelvic filling without bladder contraction."

Lists complete renal duplication among co-occurring anatomical features that worsen the prognosis.

Bladder and Bowel Dysfunction Functional abnormality of the bladder HP:0000009

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"Patients with VUR with bladder or bowel dysfunction are at a higher risk of developing infections despite continuous prophylaxis and have a much lower rate of spontaneous resolution (31% compared to 61%) and reduced success rates after endoscopic VUR surgical procedures."

Quantifies the modifying effect of bladder-bowel dysfunction.

🧬

Genetic Associations

5

ROBO2

Gene: ROBO2 hgnc:10250 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:17357069 SUPPORT Human Clinical

"In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families."

Familial segregation of ROBO2 variants with VUR.

PMID:26408188 SUPPORT Human Clinical

"In conclusion, familial PVUR is due to rare variants in TNXB and ROBO2 in 12% of all families with familial PVUR studied in this cohort."

Quantifies the combined TNXB/ROBO2 yield in a familial primary-VUR cohort.

PMID:19959718 SUPPORT Human Clinical

"We tested for but did not detect association with six candidate genes (AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A)."

Scope limit: ROBO2 is a rare-variant cause in individual families, but common ROBO2 variation showed no association with VUR in a large case-control and family-based analysis.

SOX17

Gene: SOX17 hgnc:18122 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:20960469 SUPPORT Human Clinical

"One mutation, c.775T>A (p.Y259N), recurred in six patients."

Recurrent SOX17 allele in CAKUT/VUR patients.

PMID:20960469 SUPPORT In Vitro

"Transfection studies indicated a 5-10-fold increase in the levels of the mutant protein relative to wild-type SOX17 in transfected kidney cells."

Functional data showing the mutant protein accumulates, the proposed mechanism of excess Wnt antagonism.

TNXB

Gene: TNXB hgnc:11976 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:23620400 SUPPORT Human Clinical

"This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family."

Segregation of TNXB variants with familial VUR in two families.

PMID:34059960 SUPPORT Human Clinical

"PAX2 mutation carriers (HR 5.1, 95% CI 1.3-20.0; P = 0.02) and TNXB mutation carriers (HR 20.3, 95% CI 2.4-168.7; P = 0.01) were associated with increased risk of progression to ESRD."

Establishes TNXB genotype as a prognostic factor for kidney failure in primary VUR.

SLIT2

Gene: SLIT2 hgnc:11086 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:34059960 SUPPORT Human Clinical

"These genes included PAX2 (n = 4), TNXB (n = 3), GATA3 (n = 3), SLIT2 (n = 3), ROBO2 (n = 2), TBX18 (n = 2), and the other 11 genes (one gene for each patient)."

SLIT2 among the recurrently mutated genes in an exome-sequenced primary-VUR cohort.

Monogenic diagnostic yield in primary VUR

relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:34059960 SUPPORT Human Clinical

"A monogenic cause was identified in 28 patients (7.39%)."

Diagnostic yield of exome sequencing in unselected primary VUR.

PMID:26408188 SUPPORT Human Clinical

"We did not find any possible disease-causing variants in >80% of individuals with familial PVUR, thus further confirming that PVUR is genetically heterogeneous."

Most familial primary VUR remains molecularly unexplained even after targeted sequencing.

💊

Medical Actions

6

Continuous Antimicrobial Prophylaxis

Category: Therapeutic Action: continuous antibiotic prophylaxis Ontology label: Antibiotic Prophylaxis NCIT:C51993

Agent: trimethoprim-sulfamethoxazole NCIT:C909 nitrofurantoin NCIT:C29293

Low-dose continuous antibiotic prophylaxis (commonly trimethoprim-sulfamethoxazole or nitrofurantoin) while awaiting spontaneous resolution. The RIVUR randomised trial showed prophylaxis halves recurrent UTI but did NOT reduce renal scarring over 2 years, and it substantially increases trimethoprim-sulfamethoxazole resistance among breakthrough Escherichia coli isolates — the central trade-off in VUR management. Prophylaxis is not indicated in children with a normal urinary tract after a UTI.

Mechanism Target:

INHIBITS Ascending Infection and Acute Pyelonephritis

Target Phenotypes: Recurrent urinary tract infections HP:0000010

Show evidence (3 references)

PMID:24795142 SUPPORT Human Clinical

"Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo"

Randomised evidence that prophylaxis roughly halves recurrent UTI in children with VUR (relative risk 0.55).

PMID:24795142 SUPPORT Human Clinical

"Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring."

Qualifies the benefit: infection prevention does not translate into prevention of the renal lesion, consistent with a substantial congenital component of reflux nephropathy.

PMID:24795142 SUPPORT Human Clinical

"Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group."

Documents the antimicrobial-resistance cost that qualifies the benefit of prophylaxis.

Bladder and Bowel Dysfunction Management

Category: Therapeutic Action: behavioral counseling Ontology label: Behavioral Counseling NCIT:C181743

Timed voiding, laxative treatment of constipation, pelvic floor therapy, behavioural modification and, where indicated, anticholinergics. Addressing bladder-bowel dysfunction lowers infection risk and improves spontaneous resolution, and should precede any consideration of anti-reflux surgery.

Target Phenotypes: Functional abnormality of the bladder HP:0000009

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"Treatment for bladder or bowel dysfunction, including timed voiding, laxatives, pelvic floor therapy and exercises, behavioral modifications, and anticholinergic therapy, effectively reduces voiding symptoms, improves bladder function, and increases spontaneous resolution."

Documents the components and the benefit of bladder-bowel dysfunction management.

Ureteral Reimplantation (Anti-Reflux Surgery)

Category: Therapeutic Action: ureteral reimplantation Ontology label: Reimplantation NCIT:C101242

Open, laparoscopic or robotic ureteric reimplantation lengthens the intramural tunnel and restores the flap valve. It is reserved for breakthrough febrile infections, progressive renal damage or persistent high-grade reflux, and reduces the frequency of acute pyelonephritic episodes, though older comparative studies did not show a lower overall UTI recurrence rate than medical management.

Mechanism Target:

RESTORES Ureterovesical Junction Incompetence

Show evidence (1 reference)

PMID:3153345 SUPPORT Other

"Prospective studies have not shown different recurrence rates of urinary tract infections in medically managed compared with surgically managed children. The frequency of acute pyelonephritic attacks decreased significantly after operation."

Supports a specific benefit of surgery (fewer pyelonephritic attacks) while refuting a general reduction in UTI recurrence; hence PARTIAL.

Endoscopic Subureteric Injection

Category: Therapeutic Action: endoscopic subureteric bulking-agent injection Ontology label: Surgical Procedure NCIT:C15329

Agent: dextranomer/hyaluronic acid copolymer bulking agent CHEBI:16336

Cystoscopic injection of a bulking agent (dextranomer/hyaluronic acid copolymer) under the ureteric orifice to coapt the distal ureter. It is less invasive than reimplantation but, per current clinical guidance, offers no significant advantage over antibiotic prophylaxis for preventing new UTIs or renal scarring in most patients and carries its own procedural risks.

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"However, endoscopic treatment does not offer significant advantages over antibiotic prophylaxis in preventing new UTIs or renal scarring in most patients."

Qualifies the role of endoscopic treatment; it is an option rather than a superior therapy.

Surveillance and Expectant Management

Category: Monitoring Action: supportive care Ontology label: Supportive Care NCIT:C15747

Because most primary VUR resolves spontaneously, the default approach in infants is close monitoring for UTI, renal growth and kidney damage, with escalation only for recurrent infection, progressive damage or inadequate renal growth.

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"Generally, the most effective approach to managing VUR in infants involves closely monitoring them for UTIs and kidney damage."

Establishes expectant management as the default in infants.

Genetic Counseling and Family Evaluation

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counselling should convey the high familial recurrence (roughly one third of siblings, up to two thirds of offspring of an affected mother), the marked locus heterogeneity that limits molecular diagnosis, and the resulting role of imaging-based rather than gene-based family evaluation.

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"A genetic predisposition for the disorder exists, as up to two-thirds of children born to women with primary VUR will also exhibit the condition."

The recurrence figure that underpins family counselling.

🔬

Diagnosis

3

Voiding Cystourethrography (VCUG)

Direct contrast cystography during voiding is the diagnostic gold standard; it demonstrates reflux, allows International Reflux Study grading (I-V), and shows associated anatomy (duplication, diverticula, urethral abnormalities).

voiding cystourethrography NCIT:C38049

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"the gold standard for evaluating VUR is direct cystography with voiding cystourethrogram (VCUG)"

Establishes VCUG as the reference diagnostic test.

Renal Ultrasonography

First-line imaging for renal anatomy, cortical thickness and hydronephrosis; it cannot however exclude high-grade reflux.

renal ultrasound NCIT:C159885

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"Unfortunately, ultrasound lacks high sensitivity or specificity for detecting high-grade VUR."

Defines the role and the limitation of ultrasound in the VUR diagnostic pathway.

Sibling and Offspring Screening

Because of the high familial recurrence, baseline renal ultrasound is recommended for siblings of an affected child, particularly those aged 3 or younger, with VCUG reserved for those with an abnormal ultrasound or a UTI. Routine screening of asymptomatic siblings with a normal ultrasound is not currently recommended.

renal ultrasound NCIT:C159885

Show evidence (2 references)

PMID:33085409 SUPPORT Other

"Baseline ultrasound imaging for siblings of patients with VUR is recommended, as their incidence of VUR is reported to be between 27% and 46%, particularly in those children aged 3 or younger."

Supports the family-screening recommendation that follows from the familial nature of the disease.

PMID:33085409 SUPPORT Other

"Among siblings, the incidence of VUR is about 30%, although routine screening of asymptomatic siblings with normal renal ultrasound examinations is presently not recommended."

Documents the limit of the screening recommendation; hence PARTIAL.

📈

Progression

3

Spontaneous resolution of low-grade reflux

Age: Birth to 5 years

Primary VUR frequently resolves as the child grows and the intramural ureteric tunnel lengthens. About 70-80% of grade I-II reflux resolves by age 5. This natural history is the reason management is predominantly expectant in infancy.

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"About 75% (70% to 80%) of children with grade I and II VUR will spontaneously resolve their VUR by age 5."

Quantifies resolution in low-grade reflux.

Persistent high-grade or bilateral reflux

Age: Over 5 years

Grades III-IV resolve in 60-70% over 5 years when unilateral and discovered before age 2, but only 10-20% in children over 5 with bilateral reflux, and grade V rarely resolves without surgery. These are the children in whom intervention is considered.

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"However, in children over age 5 with bilateral VUR, the rate of spontaneous resolution drops to only 10% to 20% over 5 years. For patients with grade V disease, spontaneous resolution without surgical intervention is rare."

Quantifies the poor resolution of high-grade, bilateral reflux.

Ongoing renal scar accrual

New renal scars continue to form beyond 5 years of age and can occur at any reflux grade, so surveillance cannot be discontinued simply on the basis of age or low grade.

Show evidence (1 reference)

PMID:3153345 SUPPORT Other

"Contrary to earlier reports, a recent survey has documented that new scars in children develop with significant frequency beyond 5 years of age."

Documents late scar accrual.

📊

Prevalence

3

Newborns (all-cause vesicoureteral reflux, general population)

Birth Prevalence 1000.0 per 100,000 >1 in 1,000

Approximately 1% of newborns; older white-population estimates give 1-2%. This is the prevalence of primary VUR overall; the fraction of that total that is familial is not established, so the number should be read as an upper bound on the prevalence of familial VUR rather than an estimate of it.

Show evidence (2 references)

PMID:33085409 SUPPORT Human Clinical

"VUR is the most prevalent urological abnormality in neonates, occurring in approximately 1% of all newborns."

Population prevalence of VUR in newborns.

PMID:10739767 SUPPORT Human Clinical

"Primary vesicoureteric reflux (VUR) affects 1%-2% of whites, and reflux nephropathy (RN) causes up to 15% of end-stage renal failure in children and adults."

Independent estimate of 1-2% in white populations.

Siblings of an index case

Point Prevalence 30000.0 per 100,000 (27000.0–46000.0) >1 in 1,000

Sibling recurrence risk is roughly 30% (reported range 27-46%, highest in children aged 3 years or younger) — the core epidemiological evidence for a strong genetic contribution.

Show evidence (2 references)

PMID:33085409 SUPPORT Human Clinical

"Baseline ultrasound imaging for siblings of patients with VUR is recommended, as their incidence of VUR is reported to be between 27% and 46%, particularly in those children aged 3 or younger."

Quantifies the sibling recurrence range.

PMID:21441121 SUPPORT Human Clinical

"VUR appears to be an inherited condition and is reported in approximately one third of siblings of index cases."

Independent estimate of the sibling recurrence risk.

Offspring of an affected parent

Point Prevalence 50000.0 per 100,000 (up to 66000.0) >1 in 1,000

Vertical transmission approaches 50% in the largest family series, with reports of up to two-thirds among children of affected mothers; the central estimate is set at the ~50% transmission rate and the two-thirds figure is recorded as the upper bound.

Show evidence (2 references)

PMID:29097723 SUPPORT Human Clinical

"Primary VUR is familial, with transmission rate and sibling risk both approaching 50%, and appears highly genetically heterogeneous."

Source of the central ~50% parent-to-child transmission estimate, from the largest genetic study of VUR.

PMID:33085409 SUPPORT Other

"A genetic predisposition for the disorder exists, as up to two-thirds of children born to women with primary VUR will also exhibit the condition."

Supports the upper bound only; the source states "up to" two-thirds, so it cannot be read as a point estimate.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Familial Vesicoureteral Reflux:

Secondary vesicoureteral reflux

Overlapping Features Reflux caused by elevated intravesical pressure or an anatomically abnormal bladder outlet — posterior urethral valves, neurogenic bladder (spina bifida), bladder exstrophy, urinary outlet obstruction. Distinguished by the presence of the underlying obstructive or neurological lesion on cystography and urodynamics.

Show evidence (1 reference)

PMID:33085409 SUPPORT Other

"VUR may also be associated with other congenital conditions such as posterior urethral valves, neurogenic bladder, spina bifida, urinary outlet obstruction, bladder overactivity, imperforate anus, ureterocele, and bladder exstrophy."

Lists the conditions that produce secondary VUR.

Syndromic CAKUT with vesicoureteral reflux

Overlapping Features VUR as one feature of a defined multisystem disorder — renal coloboma syndrome (PAX2), branchio-oto-renal syndrome, urofacial (Ochoa) syndrome, prune belly syndrome, exstrophy-epispadias complex. Suspected when extrarenal features are present; extrarenal manifestations more than double the monogenic diagnostic yield.

Show evidence (1 reference)

PMID:34059960 SUPPORT Human Clinical

"There was a significant difference in the rate of gene mutations between patients with or without extrarenal complications (14.1% vs. 6%, P = 0.035)."

Extrarenal features substantially raise the probability of an identifiable (often syndromic) monogenic cause.

🔬

Clinical Trials

1

NCT00405704 PHASE_III COMPLETED

Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR): a 2-year, multisite, randomized, placebo-controlled trial of trimethoprim-sulfamethoxazole prophylaxis in 607 children with VUR diagnosed after a first or second febrile or symptomatic urinary tract infection.

Target Phenotypes: Recurrent urinary tract infections HP:0000010 Renal cortical atrophy HP:0002048

Show evidence (2 references)

PMID:24795142 SUPPORT Human Clinical

"In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim-sulfamethoxazole prophylaxis in preventing..."

Describes the RIVUR trial design and population.

clinicaltrials:NCT00405704 SUPPORT Human Clinical

"Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance."

ClinicalTrials.gov registration confirming the trial identity and its pre-specified secondary outcomes, including the renal-scarring endpoint that the trial did not meet.

🐁

Animal Models

3

Robo2 heterozygous and mosaic loss-of-function mutants mouse (Mus musculus) Gene-dosage loss-of-function model

Reducing Robo2 gene dosage in mice reproduces the human CAKUT-VUR phenotype, supplying the in vivo evidence that SLIT-ROBO signalling controls ureteric bud position and ureterovesical junction competence. Recapitulates the human VUR2 subtype.

Species

mouse (Mus musculus)

Genotype

Robo2 heterozygous and mosaic loss-of-function mutants

Genes

ROBO2 hgnc:10250

Show evidence (1 reference)

PMID:17357069 SUPPORT Model Organism

"Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes."

Direct statement of phenotype recapitulation in the Robo2 dosage model.

Robo2(PB/+) Gen1(PB/+) digenic piggyBac insertional mutants mouse (Mus musculus) Digenic insertional-mutagenesis model

A digenic model in which Robo2 and Gen1 co-regulate ureteric bud germination through MAPK/ERK; prenatal MEK inhibition with U0126 prevents the CAKUT phenotype. Limitation: the model is engineered and digenic, the rescue requires systemic MEK inhibition during pregnancy, and no human VUR has been shown to be MAPK/ERK-driven, so this is a mechanistic probe rather than a therapeutic model (see the HUMAN_MODEL_MISMATCH discussion).

Species

mouse (Mus musculus)

Genotype

Robo2(PB/+) Gen1(PB/+) digenic piggyBac insertional mutants

Genes

ROBO2 hgnc:10250

Show evidence (1 reference)

PMID:36870240 SUPPORT Model Organism

"Intraperitoneal injection of U0126 during pregnancy prevented the development of the CAKUT phenotype in Robo2PB/+Gen1PB/+ mice."

Defines the model and its pharmacological rescue.

C3H/HeOuJ, an immunocompetent inbred strain with native vesicoureteral reflux, transurethrally inoculated with uropathogenic Escherichia coli mouse (Mus musculus) Infection model on a refluxing genetic background

The standard experimental model of acquired reflux nephropathy: mice that natively have vesicoureteral reflux develop renal mucosal injury, tubulointerstitial nephritis and cortical fibrosis after ascending uropathogenic E. coli infection, with the degree of fibrosis tracking the degree of leukocyte recruitment rather than bacterial burden alone.

Species

mouse (Mus musculus)

Genotype

C3H/HeOuJ, an immunocompetent inbred strain with native vesicoureteral reflux, transurethrally inoculated with uropathogenic Escherichia coli

Show evidence (2 references)

PMID:27760770 SUPPORT Model Organism

"This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis."

Explicit statement of phenotype recapitulation against human acquired renal scarring.

PMID:33148615 SUPPORT Model Organism

"We used a preclinical model of uropathogenic Escherichia coli-induced acute pyelonephritis to determine the contribution of neutrophils and monocytes to resolution of the condition and the subsequent development of kidney fibrosis."

Describes the same model used to dissect the leukocyte contribution to scarring.

{ }

Source YAML

click to show

name: Familial Vesicoureteral Reflux
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: familial vesicoureteral reflux
  term:
    id: MONDO:0017329
    label: familial vesicoureteral reflux
synonyms:
- familial VUR
- hereditary vesicoureteral reflux
- primary nonsyndromic vesicoureteric reflux
- familial primary vesicoureteric reflux
parents:
- hereditary disease
- vesicoureteral reflux
description: >
  Familial vesicoureteral reflux (VUR) is the familial occurrence of primary,
  non-syndromic retrograde flow of urine from the bladder into the ureter and,
  in higher grades, into the renal pelvis and collecting ducts. The proximate
  defect is a congenitally incompetent ureterovesical junction: an abnormally
  positioned, laterally displaced ureteric orifice with a short intramural
  (submucosal) ureteric tunnel that cannot be compressed against the detrusor
  during bladder filling and voiding, so the normal flap-valve fails.
  Developmentally the defect is traced to an abnormal site of ureteric bud
  outgrowth from the nephric (Wolffian) duct, which both misplaces the future
  ureteric orifice and, because the bud then contacts an inappropriate region of
  metanephric mesenchyme, can produce co-existing renal hypodysplasia. This
  explains why the renal lesion in VUR ("reflux nephropathy") is partly
  congenital (dysplasia) and partly acquired (post-pyelonephritic cortical
  scarring), and why renal damage is not fully preventable by controlling
  infection. Familial aggregation is strong — roughly one third of siblings and
  up to two thirds of offspring of an affected mother are affected — and
  transmission in many kindreds resembles autosomal dominant inheritance with
  incomplete penetrance and variable expressivity, though the condition is
  highly locus-heterogeneous and in most families no single gene is found. The
  OMIM phenotypic series (PS193000) recognises eight autosomal loci, VUR1-VUR8,
  of which three have an identified gene: ROBO2 (VUR2), SOX17 (VUR3) and TNXB
  (VUR8); an X-linked form is also described. VUR sits within the spectrum of
  congenital anomalies of the kidney and urinary tract (CAKUT), and reflux
  nephropathy remains a leading cause of childhood hypertension and of kidney
  failure in children and young adults.
notes: >
  Scope: this entry models PRIMARY, non-syndromic, familial VUR. Secondary VUR
  arising from bladder outlet obstruction (posterior urethral valves),
  neurogenic bladder, or as one feature of a defined multisystem syndrome
  (renal coloboma/PAX2, branchio-oto-renal, Ochoa/urofacial, prune belly,
  exstrophy-epispadias, 22q11.2 deletion) is out of scope and is curated on the
  respective syndrome entries. Bladder and bowel dysfunction is modelled here as
  a modifying co-factor rather than as a cause, since in primary VUR it worsens
  infection risk and lowers spontaneous-resolution rates but is not the
  originating lesion. No GeneReviews chapter exists for familial vesicoureteral
  reflux (a PubMed search for "vesicoureteral reflux"[TI] AND GeneReviews
  returned no results on 2026-08-01), so the phenotype baseline here is drawn
  from the primary literature plus a current clinical reference review. A
  claude_code deep-research run was performed
  (research/Familial_Vesicoureteral_Reflux-deep-research-claude_code.md) but
  returned only a short ontology-verification addendum rather than a full
  narrative; every claim in this entry was therefore anchored directly on
  primary literature fetched and snippet-verified against cached abstracts.

references:
- reference: PMID:33085409
  title: "Vesicoureteral Reflux."
- reference: PMID:16433689
  title: "Vesicoureteric reflux and renal malformations: a developmental problem."

inheritance:
- name: Autosomal dominant with incomplete penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >
    Many multigenerational VUR kindreds segregate the trait in a pattern
    consistent with autosomal dominant inheritance with reduced penetrance and
    highly variable expressivity (grade, laterality, and presence of reflux
    nephropathy all vary within a pedigree). Dominant-model parametric linkage
    underpins the VUR1 (1p13) and 10q26 signals. A 2q37 dominant locus is also
    reported in the linkage literature but has no OMIM VUR series number and is
    not modelled as a subtype here.
  evidence:
  - reference: PMID:19443636
    reference_title: "A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance."
    explanation: >
      States that the mapped primary-VUR loci (1p13 and 2q37) were identified
      under an autosomal dominant model. Note this is the background framing of
      prior scans, not a result of this paper, whose own dominant-model analysis
      was negative.
  - reference: PMID:29097723
    reference_title: "Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "parametric linkage analysis of 460 families (1062 affected individuals) under a dominant model identified a single region, on 10q26, that showed strong linkage (HLOD = 4.90; ZLRLOD = 4.39) to VUR"
    explanation: >
      The largest VUR linkage study to date obtained its only significant signal
      under a dominant model, supporting dominant transmission in a subset of
      families.
  - reference: PMID:1623385
    reference_title: "Vesicoureteric reflux in sibships."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis suggests that most instances of familial vesicoureteric reflux arise secondary to expression of autosomal dominant single genes with incomplete penetrance."
    explanation: >
      Direct support for the structured penetrance qualifier: segregation
      analysis of a sibship in which reflux skipped the preceding and succeeding
      generations concluded that dominant alleles with incomplete penetrance
      explain most familial VUR.
- name: Autosomal recessive (VUR7 kindreds)
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Absence of reflux in the parents of many affected children prompted testing
    of a recessive model, which uncovered the chromosome 12p11-q13 (VUR7) locus
    across pedigrees of several ancestries.
  evidence:
  - reference: PMID:19443636
    reference_title: "A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping."
    explanation: >
      Directly documents recessive inheritance of a major primary-VUR locus.
- name: Polygenic and multifactorial contribution
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  description: >
    In most families no single Mendelian locus is identified; sib-pair and
    genome-wide association analyses point to multiple contributing loci of
    small effect superimposed on the familial clustering.
  evidence:
  - reference: PMID:19959718
    reference_title: "Whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations."
    explanation: >
      A large linkage/association scan failed to find major loci, favouring an
      oligogenic/polygenic architecture in most families.
  - reference: PMID:19690587
    reference_title: "A genome scan in affected sib-pairs with familial vesicoureteral reflux identifies a locus on chromosome 5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggested that multiple genes are likely to contribute to the formation of VUR phenotype."
    explanation: >
      Affected sib-pair analysis identified three independent linkage peaks,
      supporting a multigenic contribution.

has_subtypes:
- name: VUR1
  display_name: Vesicoureteral reflux 1 (VUR1, 1p13 locus)
  subtype_term:
    preferred_term: vesicoureteral reflux 1
    term:
      id: MONDO:0008653
      label: vesicoureteral reflux 1
  description: >
    The first mapped familial VUR locus, on chromosome 1p13, defined by the
    original genome-wide search in seven European families with apparently
    dominant inheritance of VUR and reflux nephropathy. The causal gene has not
    been identified. OMIM 193000 is the index entry of the VUR phenotypic
    series.
  evidence:
  - reference: PMID:10739767
    reference_title: "Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most positive locus spanned 20 cM on 1p13 between GATA176C01 and D1S1653 and had a nonparametric LOD score (NPL) of 5.76 (P=.0002) and a parametric LOD score of 3.16."
    explanation: >
      Defines the VUR1 locus interval on 1p13 with genome-wide significant
      linkage.
  - reference: PMID:19959718
    reference_title: "Whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We found modest evidence of linkage but no clear overlap with previous studies."
    explanation: >
      Counter-evidence: a much larger whole-genome scan did not replicate the
      earlier VUR linkage peaks, so VUR1 (and by the same argument the
      sib-pair-derived VUR4/VUR5/VUR6 loci) should be read as unreplicated
      mapping results, not as established disease loci.
- name: VUR2
  display_name: Vesicoureteral reflux 2 (VUR2, ROBO2)
  subtype_term:
    preferred_term: vesicoureteral reflux 2
    term:
      id: MONDO:0012573
      label: vesicoureteral reflux 2
  description: >
    VUR caused by disruption of ROBO2 (3p12.3), the receptor for SLIT ligands.
    Identified through a de novo t(Y;3) translocation disrupting ROBO2 in a man
    with severe bilateral VUR and ureterovesical junction defects, with
    segregating intracellular missense variants in two further CAKUT/VUR
    families. Rare ROBO2 variants account for roughly 3% of familial primary
    VUR families in the largest sequenced cohort.
  subtype_frequency: about 3% of familial primary VUR families
  genes:
  - preferred_term: ROBO2
    term:
      id: hgnc:10250
      label: ROBO2
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:17357069
      reference_title: "Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families."
      explanation: >
        Heterozygous ROBO2 variants segregating with disease in two families
        support dominant transmission of VUR2.
  evidence:
  - reference: PMID:17357069
    reference_title: "Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro."
    explanation: >
      Establishes ROBO2 disruption as the lesion underlying this VUR subtype.
- name: VUR3
  display_name: Vesicoureteral reflux 3 (VUR3, SOX17)
  subtype_term:
    preferred_term: vesicoureteral reflux 3
    term:
      id: MONDO:0013356
      label: vesicoureteral reflux 3
  description: >
    VUR associated with mutation of SOX17 (8q11.23), an HMG-box transcription
    factor and Wnt/beta-catenin antagonist. The recurrent p.Y259N allele
    accumulates as protein and produces excessive inhibition of Wnt signalling
    during kidney and urinary tract development.
  genes:
  - preferred_term: SOX17
    term:
      id: hgnc:18122
      label: SOX17
  evidence:
  - reference: PMID:20960469
    reference_title: "Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified mutations in SOX17, an HMG-box transcription factor and Wnt signaling antagonist, in eight patients with CAKUT (seven vesico-ureteric reflux, one pelvic obstruction)."
    explanation: >
      Documents SOX17 mutation in patients whose predominant CAKUT phenotype is
      vesicoureteric reflux.
- name: VUR4
  display_name: Vesicoureteral reflux 4 (VUR4, chromosome 5 locus)
  subtype_term:
    preferred_term: vesicoureteral reflux 4
    term:
      id: MONDO:0013682
      label: vesicoureteral reflux 4
  description: >
    Susceptibility locus on chromosome 5 identified by affected sib-pair
    analysis of 98 multiplex familial VUR families; the strongest of three peaks
    in that scan (LOD > 4). No causal gene has been identified.
  evidence:
  - reference: PMID:19690587
    reference_title: "A genome scan in affected sib-pairs with familial vesicoureteral reflux identifies a locus on chromosome 5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a genome-wide statistically significant linkage peak with an LOD score greater than 4 on chromosome 5 and two linkage peaks with LOD scores greater than 3.6 on chromosomes 13 and 18 were identified in these 98 families"
    explanation: >
      Defines the chromosome 5 locus that OMIM designates VUR4.
- name: VUR5
  display_name: Vesicoureteral reflux 5 (VUR5, chromosome 13 locus)
  subtype_term:
    preferred_term: vesicoureteral reflux 5
    term:
      id: MONDO:0013683
      label: vesicoureteral reflux 5
  description: >
    Susceptibility locus on chromosome 13 from the same affected sib-pair scan
    (LOD > 3.6). No causal gene has been identified.
  evidence:
  - reference: PMID:19690587
    reference_title: "A genome scan in affected sib-pairs with familial vesicoureteral reflux identifies a locus on chromosome 5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two linkage peaks with LOD scores greater than 3.6 on chromosomes 13 and 18 were identified in these 98 families"
    explanation: >
      Defines the chromosome 13 locus that OMIM designates VUR5.
- name: VUR6
  display_name: Vesicoureteral reflux 6 (VUR6, chromosome 18 locus)
  subtype_term:
    preferred_term: vesicoureteral reflux 6
    term:
      id: MONDO:0013684
      label: vesicoureteral reflux 6
  description: >
    Susceptibility locus on chromosome 18 from the same affected sib-pair scan
    (LOD > 3.6). No causal gene has been identified.
  evidence:
  - reference: PMID:19690587
    reference_title: "A genome scan in affected sib-pairs with familial vesicoureteral reflux identifies a locus on chromosome 5."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two linkage peaks with LOD scores greater than 3.6 on chromosomes 13 and 18 were identified in these 98 families"
    explanation: >
      Defines the chromosome 18 locus that OMIM designates VUR6.
- name: VUR7
  display_name: Vesicoureteral reflux 7 (VUR7, 12p11-q13, recessive)
  subtype_term:
    preferred_term: vesicoureteral reflux 7
    term:
      id: MONDO:0014161
      label: vesicoureteral reflux 7
  description: >
    Recessively inherited primary VUR mapping to chromosome 12p11-q13. Unlike
    the other loci, it emerged only when a recessive model was tested, and it
    contributed across pedigrees of several ancestries, suggesting a relatively
    common recessive risk allele.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:19443636
      reference_title: "A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Analysis under the dominant model yielded no signals across the entire genome."
      explanation: >
        The VUR7 locus is invisible under a dominant model and appears only
        under a recessive one, defining this subtype's mode of inheritance.
  evidence:
  - reference: PMID:19443636
    reference_title: "A recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations."
    explanation: >
      Defines the recessive VUR7 locus and its cross-population contribution.
- name: VUR8
  display_name: Vesicoureteral reflux 8 (VUR8, TNXB)
  subtype_term:
    preferred_term: vesicoureteral reflux 8
    term:
      id: MONDO:0014422
      label: vesicoureteral reflux 8
  description: >
    VUR caused by heterozygous missense variants in TNXB (tenascin XB, 6p21.3),
    an extracellular matrix glycoprotein expressed in the developing
    ureterovesical junction. Affected individuals frequently also have joint
    hypermobility, reflecting the connective-tissue role of tenascin X. TNXB
    carriers in a Chinese registry had a higher hazard of progression to kidney
    failure, although that estimate rests on only three carriers and the
    confidence interval is correspondingly wide (HR 20.3, 95% CI 2.4-168.7).
    TNXB is the most common identified cause of autosomal dominant familial
    primary VUR, found in about 9% of families in the largest sequenced cohort.
  subtype_frequency: about 9% of familial primary VUR families
  genes:
  - preferred_term: TNXB
    term:
      id: hgnc:11976
      label: TNXB
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:23620400
      reference_title: "TNXB mutations can cause vesicoureteral reflux."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family."
      explanation: >
        Heterozygous TNXB missense variants segregating with disease in two
        families support dominant transmission of VUR8.
  evidence:
  - reference: PMID:23620400
    reference_title: "TNXB mutations can cause vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We obtained a significant multipoint parametric logarithm of odds score of 3.3 on chromosome 6p, and whole-exome sequencing identified a deleterious heterozygous mutation (T3257I) in the gene encoding tenascin XB (TNXB in 6p21.3)."
    explanation: >
      Establishes TNXB as the VUR8 gene by linkage plus exome sequencing in a
      hereditary VUR family.
  - reference: PMID:26408188
    reference_title: "Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all the individuals with the TNXB variants who had joint mobility examination done have significant joint hypermobility as assessed by Beighton score"
    explanation: >
      Documents the connective-tissue (joint hypermobility) feature that
      accompanies TNXB-related familial VUR.
- name: VURX
  display_name: Vesicoureteral reflux, X-linked (VURX)
  subtype_term:
    preferred_term: vesicoureteral reflux, X-linked
    term:
      id: MONDO:0010755
      label: vesicoureteral reflux, X-linked
  description: >
    A rare X-linked form of familial vesicoureteral reflux recognised as a
    distinct OMIM entry (314550) outside the autosomal VUR1-VUR8 series, based
    on isolated pedigrees in which only male relatives connected through
    unaffected females are affected. No causal gene has been identified, and the
    overall evidence for X linkage in VUR is weak: male-to-male transmission and
    the female predominance of VUR argue against it, so this subtype is retained
    for completeness of the nosology rather than as an established molecular
    entity.
  inheritance:
  - name: X-linked
    inheritance_term:
      preferred_term: X-linked inheritance
      term:
        id: HP:0001417
        label: X-linked inheritance
    evidence:
    - reference: PMID:1142496
      reference_title: "Sex-linked familial reflux."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A family is described in which all 3 brothers and the maternal grandfather had vesicoureteral reflux, whereas the father, mother and 3 daughters were urologically normal."
      explanation: >
        The classic pedigree underlying the X-linked VUR designation.
    - reference: PMID:1142496
      supports: SUPPORT
      reference_title: "Sex-linked familial reflux."
      evidence_source: HUMAN_CLINICAL
      snippet: "Nevertheless, available evidence indicates that familial reflux is usually transmitted by multifactorial polygenic inheritance."
      explanation: >
        The same report cautions that X linkage is the exception, not the rule,
        in familial VUR.
  evidence:
  - reference: PMID:1142496
    reference_title: "Sex-linked familial reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This pedigree strongly suggests and X-linked mode of genetic transmission."
    explanation: >
      Original description of an apparently X-linked familial VUR pedigree
      (quoted verbatim, including the typographical error in the abstract).
  - reference: PMID:21981614
    reference_title: "Genome gender diversity in affected sib-pairs with familial vesico-ureteric reflux identified by single nucleotide polymorphism linkage analysis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "On the other hand male-to-male transmission and a higher ratio of females to males argued against X-linked inheritance."
    explanation: >
      Counter-evidence: the epidemiology of familial VUR as a whole is
      inconsistent with X-linked inheritance, so VURX remains a contested,
      pedigree-level designation.

prevalence:
- population: Newborns (all-cause vesicoureteral reflux, general population)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1000.0
  notes: >
    Approximately 1% of newborns; older white-population estimates give 1-2%.
    This is the prevalence of primary VUR overall; the fraction of that total
    that is familial is not established, so the number should be read as an
    upper bound on the prevalence of familial VUR rather than an estimate of
    it.
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "VUR is the most prevalent urological abnormality in neonates, occurring in approximately 1% of all newborns."
    explanation: Population prevalence of VUR in newborns.
  - reference: PMID:10739767
    reference_title: "Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary vesicoureteric reflux (VUR) affects 1%-2% of whites, and reflux nephropathy (RN) causes up to 15% of end-stage renal failure in children and adults."
    explanation: Independent estimate of 1-2% in white populations.
- population: Siblings of an index case
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 30000.0
  rate_low: 27000.0
  rate_high: 46000.0
  notes: >
    Sibling recurrence risk is roughly 30% (reported range 27-46%, highest in
    children aged 3 years or younger) — the core epidemiological evidence for a
    strong genetic contribution.
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Baseline ultrasound imaging for siblings of patients with VUR is recommended, as their incidence of VUR is reported to be between 27% and 46%, particularly in those children aged 3 or younger."
    explanation: Quantifies the sibling recurrence range.
  - reference: PMID:21441121
    reference_title: "Primary, nonsyndromic vesicoureteric reflux and nephropathy in sibling pairs: a United Kingdom cohort for a DNA bank."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "VUR appears to be an inherited condition and is reported in approximately one third of siblings of index cases."
    explanation: Independent estimate of the sibling recurrence risk.
- population: Offspring of an affected parent
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 50000.0
  rate_high: 66000.0
  notes: >
    Vertical transmission approaches 50% in the largest family series, with
    reports of up to two-thirds among children of affected mothers; the central
    estimate is set at the ~50% transmission rate and the two-thirds figure is
    recorded as the upper bound.
  evidence:
  - reference: PMID:29097723
    reference_title: "Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary VUR is familial, with transmission rate and sibling risk both approaching 50%, and appears highly genetically heterogeneous."
    explanation: >
      Source of the central ~50% parent-to-child transmission estimate, from the
      largest genetic study of VUR.
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A genetic predisposition for the disorder exists, as up to two-thirds of children born to women with primary VUR will also exhibit the condition."
    explanation: >
      Supports the upper bound only; the source states "up to" two-thirds, so it
      cannot be read as a point estimate.

pathophysiology:
- name: SLIT2-ROBO2 Signaling Loss
  biological_scale: MOLECULAR
  role: trigger
  description: >
    Loss or dominant-negative disruption of the ROBO2 receptor abolishes
    repulsive SLIT2-ROBO2 signalling at the caudal nephric duct. In the intact
    system this signal restricts the field in which GDNF can induce a bud, so
    its loss permits ectopic and supernumerary ureteric bud outgrowth. This is
    the proximal molecular lesion of VUR2.
  molecular_functions:
  - preferred_term: transmembrane signaling receptor activity
    term:
      id: GO:0004888
      label: transmembrane signaling receptor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: Roundabout signaling pathway
    term:
      id: GO:0035385
      label: Roundabout signaling pathway
    modifier: DECREASED
  genes:
  - preferred_term: ROBO2
    term:
      id: hgnc:10250
      label: ROBO2
  - preferred_term: SLIT2
    term:
      id: hgnc:11086
      label: SLIT2
  evidence:
  - reference: PMID:17357069
    reference_title: "Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro."
    explanation: >
      Functional demonstration that the patient ROBO2 alleles abolish SLIT-ROBO
      signalling, defining the molecular lesion.
  downstream:
  - target: Abnormal Ureteric Bud Outgrowth Position

- name: SOX17 Gain of Wnt Antagonism
  biological_scale: MOLECULAR
  role: trigger
  description: >
    The recurrent SOX17 p.Y259N allele is not a null: the mutant protein
    accumulates several-fold above wild type and, being a Wnt/beta-catenin
    antagonist, delivers a correspondingly excessive brake on canonical Wnt
    signalling during kidney and urinary tract development. This is the proximal
    molecular lesion of VUR3.
  molecular_functions:
  - preferred_term: DNA-binding transcription factor activity
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: negative regulation of canonical Wnt signaling pathway
    term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    modifier: INCREASED
  genes:
  - preferred_term: SOX17
    term:
      id: hgnc:18122
      label: SOX17
  evidence:
  - reference: PMID:20960469
    reference_title: "Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection studies indicated a 5-10-fold increase in the levels of the mutant protein relative to wild-type SOX17 in transfected kidney cells."
    explanation: >
      Shows the mutant protein accumulates rather than being lost, the basis for
      an excess-antagonism (not loss-of-function) mechanism.
  downstream:
  - target: Abnormal Ureteric Bud Outgrowth Position

- name: Tenascin-X Focal Adhesion Defect
  biological_scale: MOLECULAR
  role: trigger
  description: >
    Missense variants in the fibronectin type III region of tenascin XB impair
    the cell-matrix coupling that TNXB normally supports. Patient fibroblasts
    show reduced motility and reduced focal adhesion kinase phosphorylation,
    consistent with defective disassembly of focal adhesions. This is the
    proximal molecular lesion of VUR8 and acts on the ureterovesical junction
    directly rather than through bud positioning.
  molecular_functions:
  - preferred_term: extracellular matrix structural constituent
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: cell-matrix adhesion
    term:
      id: GO:0007160
      label: cell-matrix adhesion
    modifier: ABNORMAL
  genes:
  - preferred_term: TNXB
    term:
      id: hgnc:11976
      label: TNXB
  evidence:
  - reference: PMID:23620400
    reference_title: "TNXB mutations can cause vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix."
    explanation: >
      Patient-derived cells define the molecular consequence of the TNXB allele.
  downstream:
  - target: Ureterovesical Junction Incompetence

- name: Abnormal Ureteric Bud Outgrowth Position
  biological_scale: TISSUE
  role: trigger
  description: >
    Primary VUR originates during the fifth week of human development, when the
    ureteric bud sprouts from the caudal nephric (Wolffian) duct. Genetic
    perturbation of the signals that fix the budding site — SLIT2-ROBO2
    repulsive guidance, GDNF/RET, and Wnt/beta-catenin (antagonised by SOX17) —
    shifts the bud cranially or laterally, or produces ectopic/duplicated buds.
    Because the bud stalk becomes the ureter and its insertion becomes the
    ureteric orifice, a misplaced bud lands laterally on the developing trigone
    with a short intramural course. The same misplacement means the bud contacts
    an inappropriate region of metanephric mesenchyme, so intrinsic renal
    hypodysplasia is generated at the same time as the refluxing ureter — the
    unified "budding position" explanation for why VUR and congenital renal
    malformation co-segregate.
  locations:
  - preferred_term: ureter
    term:
      id: UBERON:0000056
      label: ureter
  cell_types:
  - preferred_term: ureteric bud cell
    term:
      id: CL:4030066
      label: ureteric bud cell
  biological_processes:
  - preferred_term: ureteric bud formation
    term:
      id: GO:0060676
      label: ureteric bud formation
    modifier: ABNORMAL
  - preferred_term: mesonephric duct development
    term:
      id: GO:0072177
      label: mesonephric duct development
    modifier: ABNORMAL
  - preferred_term: Roundabout (SLIT-ROBO) signaling pathway
    term:
      id: GO:0035385
      label: Roundabout signaling pathway
    modifier: DECREASED
  - preferred_term: negative regulation of canonical Wnt signaling pathway
    term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    modifier: INCREASED
  genes:
  - preferred_term: ROBO2
    term:
      id: hgnc:10250
      label: ROBO2
  - preferred_term: SLIT2
    term:
      id: hgnc:11086
      label: SLIT2
  - preferred_term: SOX17
    term:
      id: hgnc:18122
      label: SOX17
  evidence:
  - reference: PMID:16433689
    reference_title: "Vesicoureteric reflux and renal malformations: a developmental problem."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Some of the gene candidates that have been identified regulate the position of ureteric budding, a critical step in both kidney and urinary tract development."
    explanation: >
      States the core developmental model — VUR genes act on ureteric bud
      positioning. Evidence source is OTHER because this is a review
      synthesising human and mouse data.
  - reference: PMID:16433689
    reference_title: "Vesicoureteric reflux and renal malformations: a developmental problem."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vesicoureteric reflux (VUR) is a congenital urinary tract defect caused by the failure of the ureter to insert correctly into the bladder."
    explanation: >
      Frames VUR as a defect of ureteric insertion rather than an acquired
      bladder problem.
  - reference: PMID:17357069
    reference_title: "Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes."
    explanation: >
      Mouse Robo2 dosage reduction reproduces the human CAKUT-VUR phenotype,
      supporting SLIT-ROBO control of bud position.
  - reference: PMID:36870240
    reference_title: "Inhibition of MAPK/ERK pathway activation rescues congenital anomalies of the kidney and urinary tract (CAKUT) in Robo2(PB/+) Gen1(PB/+) mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We previously showed that Robo2 and Gen1 coregulated the germination of ureteral buds (UB), significantly increasing CAKUT incidence."
    explanation: >
      Directly implicates Robo2 in ureteric bud germination in a mouse model of
      digenic CAKUT.
  downstream:
  - target: Ureterovesical Junction Incompetence
  - target: Congenital Renal Hypodysplasia

- name: Ureterovesical Junction Incompetence
  biological_scale: TISSUE
  role: mechanism
  description: >
    The ureterovesical junction normally acts as a passive flap valve: the
    distal ureter runs obliquely for 1-2 cm within the bladder wall between the
    mucosa and the detrusor, so rising intravesical pressure compresses the
    tunnel shut. In primary VUR the intramural tunnel is too short relative to
    ureteric diameter and the orifice is laterally displaced, so the valve fails
    and urine refluxes during filling and, above all, during voiding.
    Extracellular-matrix competence of the junction also matters: TNXB, mutated
    in VUR8, is expressed in the uroepithelium of the ureterovesical junction at
    the time it forms and is proposed to generate the tensile forces that close
    it, with patient fibroblasts showing defective focal-adhesion turnover.
  locations:
  - preferred_term: ureterovesical junction
    term:
      id: UBERON:0009973
      label: ureterovesical junction
  - preferred_term: trigone of urinary bladder
    term:
      id: UBERON:0001257
      label: trigone of urinary bladder
  cell_types:
  - preferred_term: ureter urothelial cell
    term:
      id: CL:1000706
      label: ureter urothelial cell
  - preferred_term: ureter smooth muscle cell
    term:
      id: CL:1000979
      label: ureter smooth muscle cell
  biological_processes:
  - preferred_term: ureter maturation
    term:
      id: GO:0035799
      label: ureter maturation
    modifier: ABNORMAL
  - preferred_term: cell-matrix adhesion
    term:
      id: GO:0007160
      label: cell-matrix adhesion
    modifier: ABNORMAL
  genes:
  - preferred_term: TNXB
    term:
      id: hgnc:11976
      label: TNXB
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vesicoureteral reflux (VUR) is the retrograde urine flow from the urinary bladder to the upper urinary tract, usually during voiding. A short intramural ureter often causes this abnormal backward flow of urine."
    explanation: >
      Identifies the short intramural ureter as the proximate anatomical cause
      of reflux. Evidence source is OTHER because this is a clinical reference
      review.
  - reference: PMID:23620400
    reference_title: "TNXB mutations can cause vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemical studies revealed that the human uroepithelial lining of the ureterovesical junction expresses TNXB, suggesting that TNXB may be important for generating tensile forces that close the ureterovesical junction during voiding."
    explanation: >
      Provides the molecular link between a familial VUR gene and closure of the
      ureterovesical junction.
  - reference: PMID:23620400
    reference_title: "TNXB mutations can cause vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fibroblast cell lines carrying the T3257I mutation exhibited a reduction in both cell motility and phosphorylated focal adhesion kinase expression, suggesting a defect in the focal adhesions that link the cell cytoplasm to the extracellular matrix."
    explanation: >
      Patient-derived cells show the cell-matrix adhesion defect proposed to
      underlie junction incompetence.
  - reference: PMID:26408188
    reference_title: "Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TNXB is expressed in kidneys and the urinary tract during development and it is highly expressed at a critical period when the ureterovesical junction (UVJ) is being formed"
    explanation: >
      Places TNXB expression at the right time and place to affect UVJ
      formation. Not fully independent of the preceding item: this sentence in
      Elahi 2016 restates the finding of Gbadegesin 2013 (PMID:23620400).
  downstream:
  - target: Retrograde Urine Flow and Intrarenal Reflux

- name: Congenital Renal Hypodysplasia
  biological_scale: TISSUE
  role: mechanism
  description: >
    A component of the renal lesion in familial VUR is present at birth and is
    independent of infection: because the misplaced ureteric bud induces an
    inappropriate region of metanephric mesenchyme, the kidney it induces is
    hypoplastic and/or dysplastic. This "congenital reflux nephropathy" is not
    preventable by antibiotic prophylaxis or anti-reflux surgery, and accounts
    for a substantial share of the chronic kidney disease attributed to VUR.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: metanephros development
    term:
      id: GO:0001656
      label: metanephros development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16433689
    reference_title: "Vesicoureteric reflux and renal malformations: a developmental problem."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Analysis of data from humans and mice suggests that some of the renal damage associated with VUR is congenital and is due to a kidney malformation."
    explanation: >
      Establishes the congenital (malformation) component of renal damage,
      distinct from acquired scarring.
  - reference: PMID:29097723
    reference_title: "Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite treatment improvements, associated renal lesions - congenital dysplasia, acquired scarring or both - are a common cause of childhood hypertension and renal failure."
    explanation: >
      Confirms that both a congenital dysplastic and an acquired scarring lesion
      contribute to the renal outcome.
  downstream:
  - target: Reflux Nephropathy and Progressive Nephron Loss

- name: Retrograde Urine Flow and Intrarenal Reflux
  biological_scale: ORGANISM
  role: mechanism
  description: >
    Once the flap valve fails, urine flows retrogradely up the ureter during
    voiding. In higher grades the refluxed bolus reaches the renal pelvis and
    then enters the collecting ducts (intrarenal reflux) through gaping duct
    orifices on compound papillae, which are concentrated at the upper and lower
    renal poles. Intrarenal reflux is the step that converts a ureteric problem
    into a parenchymal one, and it defines the polar distribution of the scars
    that follow. Grade (I-V, International Reflux Study) tracks the extent of
    retrograde filling and dilation and is the main determinant of both
    spontaneous resolution and scarring risk.
  locations:
  - preferred_term: renal pelvis
    term:
      id: UBERON:0001224
      label: renal pelvis
  - preferred_term: ureter
    term:
      id: UBERON:0000056
      label: ureter
  evidence:
  - reference: PMID:3153345
    reference_title: "Vesico-uretero-renal reflux and the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Primarily, only gaping collecting duct orifices, confined to compound papillae and mainly situated at the kidney poles, allow intrarenal reflux."
    explanation: >
      Defines the anatomical route of intrarenal reflux and its polar
      distribution.
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Grades III to V are considered dilating or high-grade VUR and are associated with an increased risk of UTIs and renal scarring, especially grades IV and V."
    explanation: >
      Links the degree of retrograde filling/dilation to downstream renal risk.
  downstream:
  - target: Ascending Infection and Acute Pyelonephritis
  - target: Reflux Nephropathy and Progressive Nephron Loss

- name: Ascending Infection and Acute Pyelonephritis
  biological_scale: ORGANISM
  role: trigger
  conforms_to: "fibrotic_response#Tissue Injury"
  description: >
    Reflux carries bladder urine — and any bacteria in it — into the renal
    pelvis and, via intrarenal reflux, into the parenchyma, converting cystitis
    into acute pyelonephritis. Segmental scars form only in segments that both
    receive intrarenal reflux and are exposed to bacterial infection, making
    infection the essential second hit for the acquired component of reflux
    nephropathy. Bladder and bowel dysfunction (detrusor overactivity, voiding
    postponement, constipation) markedly increases infection risk on top of the
    reflux itself. This node is the kidney-specific instance of the fibrotic
    module's dysregulated wound-healing trigger.
  locations:
  - preferred_term: cortex of kidney
    term:
      id: UBERON:0001225
      label: cortex of kidney
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: response to bacterium
    term:
      id: GO:0009617
      label: response to bacterium
    modifier: INCREASED
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:3153345
    reference_title: "Vesico-uretero-renal reflux and the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These scars are confined to segments with intrarenal reflux which are, in addition, exposed to bacterial infection."
    explanation: >
      Establishes infection plus intrarenal reflux as the joint requirement for
      the acquired scar.
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with VUR with bladder or bowel dysfunction are at a higher risk of developing infections despite continuous prophylaxis and have a much lower rate of spontaneous resolution (31% compared to 61%) and reduced success rates after endoscopic VUR surgical procedures."
    explanation: >
      Quantifies bladder-bowel dysfunction as a modifier of infection risk and
      of resolution.
  - reference: PMID:27760770
    reference_title: "Inflammation drives renal scarring in experimental pyelonephritis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transurethral inoculation of uropathogenic Escherichia coli in C3H/HeOuJ mice leads to renal mucosal injury, tubulointerstitial nephritis, and cortical fibrosis."
    explanation: >
      In an immunocompetent mouse model that itself has vesicoureteral reflux,
      ascending uropathogenic E. coli infection produces exactly this injury
      step, establishing it as the tissue-injury trigger of the fibrotic
      cascade.
  downstream:
  - target: Renal Inflammatory Cell Recruitment

- name: Renal Inflammatory Cell Recruitment
  biological_scale: CELLULAR
  role: amplifier
  conforms_to: "fibrotic_response#Inflammatory Recruitment and Amplification"
  description: >
    Bacterial burden in the refluxing renal segment recruits neutrophils and
    monocyte-derived macrophages in proportion to that burden. Neutrophils
    control bacterial ascent, but the macrophage-dominated inflammatory response
    is strong and ineffective, and it is the extent of this inflammation — not
    the infection itself — that best predicts subsequent fibrosis. Experimental
    tipping of the neutrophil-macrophage balance towards macrophages worsens
    scarring, identifying this recruitment step as the amplifier that converts a
    treatable infection into permanent renal damage.
  locations:
  - preferred_term: cortex of kidney
    term:
      id: UBERON:0001225
      label: cortex of kidney
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: monocyte-derived macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: INCREASED
  evidence:
  - reference: PMID:27760770
    reference_title: "Inflammation drives renal scarring in experimental pyelonephritis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The extent of fibrosis correlates most significantly with inflammation at 7 and 28 days postinfection. The recruitment of neutrophils and inflammatory macrophages to infected kidneys is proportional to renal bacterial burden."
    explanation: >
      Directly ties leukocyte recruitment to the magnitude of subsequent renal
      fibrosis in a refluxing mouse model.
  - reference: PMID:33148615
    reference_title: "Neutrophil-Macrophage Imbalance Drives the Development of Renal Scarring during Experimental Pyelonephritis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Exacerbated macrophage-mediated inflammatory responses promoted renal scarring and compromised renal function, as indicated by elevated serum creatinine, BUN, and potassium."
    explanation: >
      Establishes the macrophage arm of the recruitment response as causal for
      scarring rather than merely correlated with it.
  downstream:
  - target: Interstitial Myofibroblast Activation

- name: Interstitial Myofibroblast Activation
  biological_scale: CELLULAR
  role: mechanism
  conforms_to: "fibrotic_response#Mesenchymal Cell Activation"
  description: >
    Macrophage-derived pro-fibrotic cytokines, principally TGF-beta, drive
    resident interstitial fibroblasts to transdifferentiate into
    alpha-smooth-muscle-actin-positive myofibroblasts, the effector cell of
    renal interstitial fibrosis. Human genetic data support a causal role for
    this axis specifically in post-UTI renal scarring: an activating TGF-beta1
    promoter allele predicts scar formation after childhood pyelonephritis
    independently of whether reflux is present.
  locations:
  - preferred_term: cortex of kidney
    term:
      id: UBERON:0001225
      label: cortex of kidney
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:19861314
    reference_title: "Functional polymorphisms in transforming growth factor-beta-1 (TGFbeta-1) and vascular endothelial growth factor (VEGF) genes modify risk of renal parenchymal scarring following childhood urinary tract infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The -509 T allele in the TGFbeta-1 promoter was significantly more common in cases with renal scarring (51%) than in non-scarring patients (22.4%) and controls (23.6%) (both P < 0.0001)."
    explanation: >
      Human genetic evidence that TGF-beta1 activity is causally upstream of
      post-UTI renal scarring, supporting the TGF-beta-driven mesenchymal
      activation step in this disease rather than only in fibrosis generally.
  - reference: PMID:19861314
    reference_title: "Functional polymorphisms in transforming growth factor-beta-1 (TGFbeta-1) and vascular endothelial growth factor (VEGF) genes modify risk of renal parenchymal scarring following childhood urinary tract infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple logistic regression testing identified the presence of VUR (odds ratio 12.4, CI 3.8-40; P < 0.001) and the TGFbeta-1 -509 T allele (OR 6.1, CI 2.4-15.5; P < 0.001) as independent risk factors for renal scarring after UTI."
    explanation: >
      Places reflux and the TGF-beta1 activating allele as independent,
      multiplicative risk factors for the scarring endpoint.
  downstream:
  - target: Renal Cortical Scarring

- name: Renal Cortical Scarring
  biological_scale: TISSUE
  role: effector
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  description: >
    Activated interstitial myofibroblasts deposit excess collagen while matrix
    degradation lags, producing a wedge-shaped, polar cortical scar with
    tubulointerstitial
    fibrosis and overlying calyceal clubbing. Scar contraction can itself
    convert closed collecting-duct orifices into gaping ones, enlarging the area
    at risk and creating a self-amplifying loop; new scars continue to appear
    beyond 5 years of age.
  locations:
  - preferred_term: cortex of kidney
    term:
      id: UBERON:0001225
      label: cortex of kidney
  cell_types:
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:27760770
    reference_title: "Inflammation drives renal scarring in experimental pyelonephritis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis."
    explanation: >
      Anchors the cortical-fibrosis endpoint of this node in a model validated
      against human acquired renal scarring.
  - reference: PMID:3153345
    reference_title: "Vesico-uretero-renal reflux and the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Scar contraction and obstruction seem to be able to transform closed collecting duct orifices into gaping ones, thereby enlarging the parenchymal area prone to intrarenal reflux and to renal scarring."
    explanation: >
      Documents the self-amplifying loop between scarring and further intrarenal
      reflux.
  - reference: PMID:3153345
    reference_title: "Vesico-uretero-renal reflux and the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There is a greater tendency for scarring to develop with more severe VUR, but new renal scars can develop with all grades of VUR."
    explanation: >
      Grades the scarring risk and shows it is not confined to high-grade
      reflux. Evidence source is OTHER because Olbing 1987 is a narrative
      review of clinical and experimental data rather than a primary cohort
      report.
  - reference: PMID:23620400
    reference_title: "TNXB mutations can cause vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary vesicoureteral reflux (VUR) is the most common congenital anomaly of the kidney and the urinary tract, and it is a major risk factor for pyelonephritic scarring and CKD in children."
    explanation: >
      Establishes pyelonephritic scarring as the key intermediate to CKD in
      primary VUR.
  downstream:
  - target: Reflux Nephropathy and Progressive Nephron Loss
  - target: Retrograde Urine Flow and Intrarenal Reflux
    evidence:
    - reference: PMID:3153345
      reference_title: "Vesico-uretero-renal reflux and the kidney."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Scar contraction and obstruction seem to be able to transform closed collecting duct orifices into gaping ones, thereby enlarging the parenchymal area prone to intrarenal reflux and to renal scarring."
      explanation: >
        A feed-back edge: established scars widen the papillary orifices, so
        more of the parenchyma becomes exposed to intrarenal reflux. This is why
        scarring in VUR is self-amplifying rather than a single-pass injury.

- name: Reflux Nephropathy and Progressive Nephron Loss
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "fibrotic_response#Architectural Distortion and Organ Dysfunction"
  description: >
    The combined congenital (hypodysplastic) and acquired (post-pyelonephritic
    scarring) lesions reduce functioning nephron mass. Reflux nephropathy is a
    leading cause of childhood hypertension and contributes roughly 10-15% of
    kidney failure requiring dialysis or transplantation in children and young
    adults.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:19959718
    reference_title: "Whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary vesicoureteric reflux accounts for approximately 10% of kidney failure requiring dialysis or transplantation, and sibling studies suggest a large genetic component."
    explanation: >
      Quantifies the contribution of primary VUR to kidney failure.
  - reference: PMID:17357069
    reference_title: "Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults."
    explanation: >
      Independent estimate of the share of ESRD attributable to reflux
      nephropathy.
  - reference: PMID:34059960
    reference_title: "Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty-eight patient (23.2%) exhibited impaired renal function at their last visit, and 18 of them (20.5%) developed ESRD at the median age of 7.0 (IQR 0.9-11.4) years."
    explanation: >
      Registry data on the frequency and timing of kidney failure in primary
      VUR.
  notes: >
    The classical textbook account of progression beyond this point — surviving
    nephrons hyperfiltering, producing proteinuria and secondary focal
    segmental glomerulosclerosis with renin-angiotensin activation and a
    self-sustaining GFR decline that continues after the reflux itself has
    resolved — is the general remnant-nephron model rather than a
    VUR-specific finding, and is recorded here as a note because no
    VUR-specific citation with a verifiable quote has been curated for it.

phenotypes:
- category: Renal
  name: Primary Vesicoureteral Reflux
  description: >
    Retrograde flow of urine from the bladder into the ureter, and in dilating
    grades into the renal pelvis and calyces, in the absence of bladder outlet
    obstruction or a neuropathic bladder. This is the defining phenotype.
  phenotype_term:
    preferred_term: Primary vesicoureteral reflux
    term:
      id: HP:0033738
      label: Primary vesicoureteral reflux
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vesicoureteral reflux (VUR) is the retrograde urine flow from the urinary bladder to the upper urinary tract, usually during voiding."
    explanation: Defines the cardinal phenotype.
- category: Renal
  name: High-Grade (Dilating) Vesicoureteral Reflux
  description: >
    Grades III-V reflux with ureteric and pyelocalyceal dilation. High-grade
    reflux carries the greatest risk of urinary tract infection and renal
    scarring and the lowest likelihood of spontaneous resolution.
  phenotype_term:
    preferred_term: High-grade vesicoureteral reflux
    term:
      id: HP:0033734
      label: High-grade vesicoureteral reflux
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Grades III to V are considered dilating or high-grade VUR and are associated with an increased risk of UTIs and renal scarring, especially grades IV and V."
    explanation: >
      Defines dilating grades and their risk profile. Frequency is deliberately
      omitted because grade distribution varies markedly with ascertainment
      (antenatal vs. post-UTI vs. sibling screening).
- category: Renal
  name: Intrarenal Reflux
  description: >
    Entry of refluxed urine into the collecting ducts through gaping orifices on
    compound papillae, predominantly at the renal poles; the anatomical
    prerequisite for pyelonephritic scarring.
  phenotype_term:
    preferred_term: Intrarenal reflux
    term:
      id: HP:0033742
      label: Intrarenal reflux
  evidence:
  - reference: PMID:3153345
    reference_title: "Vesico-uretero-renal reflux and the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Primarily, only gaping collecting duct orifices, confined to compound papillae and mainly situated at the kidney poles, allow intrarenal reflux."
    explanation: Documents intrarenal reflux and its anatomical basis.
- category: Infectious
  name: Recurrent Urinary Tract Infections
  description: >
    Recurrent, often febrile, urinary tract infections are the commonest
    presentation of familial VUR outside antenatal detection.
  phenotype_term:
    preferred_term: Recurrent urinary tract infections
    term:
      id: HP:0000010
      label: Recurrent urinary tract infections
  frequency: FREQUENT
  evidence:
  - reference: PMID:21441121
    reference_title: "Primary, nonsyndromic vesicoureteric reflux and nephropathy in sibling pairs: a United Kingdom cohort for a DNA bank."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical presentation was established in 122; 92 had urinary tract infections and 16 had abnormal antenatal renal scans."
    explanation: >
      Derived-count basis for the FREQUENT band, with both denominators stated:
      92 of the 122 patients whose mode of presentation was recorded (75%)
      presented with urinary tract infection, which is 92/407 (23%) of the full
      sibling-pair cohort. Presentation with UTI is not identical to the
      "recurrent" qualifier of HP:0000010, so the band is supported as an
      estimate of symptomatic urinary infection burden rather than as a direct
      count of recurrence.
- category: Infectious
  name: Acute Pyelonephritis
  description: >
    Febrile upper urinary tract infection resulting from reflux of infected
    bladder urine into the renal pelvis and parenchyma.
  phenotype_term:
    preferred_term: Recurrent acute pyelonephritis
    term:
      id: HP:0012787
      label: Recurrent pyelonephritis
    temporality: RECURRENT
  evidence:
  - reference: PMID:3153345
    reference_title: "Vesico-uretero-renal reflux and the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The frequency of acute pyelonephritic attacks decreased significantly after operation."
    explanation: >
      Documents acute pyelonephritis as a recurring event in VUR and its
      reduction after anti-reflux surgery.
- category: Renal
  name: Renal Cortical Scarring
  description: >
    Segmental, typically polar, wedge-shaped loss of cortex with underlying
    tubulointerstitial fibrosis and calyceal clubbing — the acquired lesion of
    reflux nephropathy, detected on DMSA scintigraphy.
  phenotype_term:
    preferred_term: Renal cortical atrophy
    term:
      id: HP:0002048
      label: Renal cortical atrophy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:24795142
    reference_title: "Antimicrobial prophylaxis for children with vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively)."
    explanation: >
      In the RIVUR randomised trial, renal scarring occurred in roughly 10-12%
      of children with VUR over 2 years, supporting the OCCASIONAL band.
- category: Renal
  name: Reflux Nephropathy
  description: >
    The combined congenital hypodysplastic and acquired scarring renal lesion of
    VUR, presenting with reduced renal size and function, proteinuria and
    hypertension.
  phenotype_term:
    preferred_term: Nephropathy
    term:
      id: HP:0000112
      label: Nephropathy
  frequency: FREQUENT
  evidence:
  - reference: PMID:21441121
    reference_title: "Primary, nonsyndromic vesicoureteric reflux and nephropathy in sibling pairs: a United Kingdom cohort for a DNA bank."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RN was radiologically proven in 223 patients."
    explanation: >
      Radiologically proven reflux nephropathy in 223 of the 407 patients (55%)
      in a UK familial-VUR sibling-pair cohort, supporting the FREQUENT band.
      Note that this cohort was ascertained through tertiary paediatric
      nephrology centres and is therefore enriched for nephropathy.
- category: Renal
  name: Renal Hypoplasia and Dysplasia
  description: >
    Small and/or dysplastic kidney present from birth, arising from induction of
    an inappropriate region of metanephric mesenchyme by the misplaced ureteric
    bud rather than from infection.
  phenotype_term:
    preferred_term: Renal hypoplasia/aplasia
    term:
      id: HP:0008678
      label: Renal hypoplasia/aplasia
  evidence:
  - reference: PMID:29097723
    reference_title: "Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite treatment improvements, associated renal lesions - congenital dysplasia, acquired scarring or both - are a common cause of childhood hypertension and renal failure."
    explanation: Documents congenital dysplasia as a component renal lesion.
- category: Renal
  name: Renal Dysplasia
  description: >
    Disorganised, maldifferentiated renal parenchyma (as distinct from a small
    but normally organised kidney), the dysplastic pole of the congenital renal
    lesion in VUR. Curated separately from HP:0008678 because that term covers
    hypoplasia/aplasia but not dysplasia.
  phenotype_term:
    preferred_term: Renal dysplasia
    term:
      id: HP:0000110
      label: Renal dysplasia
  evidence:
  - reference: PMID:16433689
    reference_title: "Vesicoureteric reflux and renal malformations: a developmental problem."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Analysis of data from humans and mice suggests that some of the renal damage associated with VUR is congenital and is due to a kidney malformation."
    explanation: >
      Supports a congenital maldevelopment (dysplastic) component of the renal
      lesion in VUR, as opposed to purely acquired scarring.
- category: Renal
  name: Chronic Kidney Disease
  description: >
    Progressive reduction in GFR from cumulative nephron loss; a minority
    progress to kidney failure requiring dialysis or transplantation, sometimes
    in childhood.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
    clinical_course: PROGRESSIVE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34059960
    reference_title: "Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty-eight patient (23.2%) exhibited impaired renal function at their last visit, and 18 of them (20.5%) developed ESRD at the median age of 7.0 (IQR 0.9-11.4) years."
    explanation: >
      Registry data: 23.2% of 379 children with primary VUR had impaired renal
      function at last visit.
- category: Renal
  name: Stage 5 Chronic Kidney Disease
  description: >
    Kidney failure requiring dialysis or transplantation. Reflux nephropathy
    accounts for roughly 10-15% of kidney failure in children and young adults
    and about 5% of paediatric kidney transplants.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  frequency: VERY_RARE
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "End-stage renal failure in children due to reflux nephropathy accounts for about 5% of all pediatric renal transplants."
    explanation: >
      Establishes the population-level contribution of reflux nephropathy to
      paediatric kidney failure. This is a population-attributable fraction over
      a transplant denominator and does not by itself give a per-patient risk;
      the frequency band is set from the cohort denominator in the next evidence
      item.
  - reference: PMID:34059960
    reference_title: "Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty-eight patient (23.2%) exhibited impaired renal function at their last visit, and 18 of them (20.5%) developed ESRD at the median age of 7.0 (IQR 0.9-11.4) years."
    explanation: >
      Derived-count basis for the VERY_RARE band: 18 of the 379 recruited
      children with primary VUR reached ESRD, i.e. 4.7% of the whole cohort.
- category: Cardiovascular
  name: Hypertension
  description: >
    Renin-mediated hypertension arising from scarred, ischaemic renal segments;
    reflux nephropathy is a classical cause of hypertension in children.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:29097723
    reference_title: "Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated renal lesions - congenital dysplasia, acquired scarring or both - are a common cause of childhood hypertension and renal failure"
    explanation: Links the renal lesions of VUR to childhood hypertension.
- category: Renal
  name: Hydronephrosis
  description: >
    Pelvicalyceal dilation, frequently the antenatal finding that prompts
    postnatal cystography; about 16% of neonates with antenatal hydronephrosis
    prove to have VUR.
  phenotype_term:
    preferred_term: Hydronephrosis
    term:
      id: HP:0000126
      label: Hydronephrosis
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A systematic review of 34 studies indicated that approximately 16% of neonates with ultrasound evidence of hydronephrosis eventually have VUR."
    explanation: Links antenatal hydronephrosis to the detection of VUR.
- category: Renal
  name: Duplicated Collecting System
  description: >
    Complete or partial ureteric duplication, a co-occurring CAKUT phenotype
    expected from an ectopic or duplicated ureteric bud and a negative predictor
    of spontaneous resolution.
  phenotype_term:
    preferred_term: Duplicated collecting system
    term:
      id: HP:0000081
      label: Duplicated collecting system
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Negative predictive factors for spontaneous resolution of VUR include female gender, higher grade reflux (grades IV and V), other ureteral abnormalities, complete renal duplication, periureteral diverticula, bladder or bowel disorders, and renal pelvic filling without bladder contraction."
    explanation: >
      Lists complete renal duplication among co-occurring anatomical features
      that worsen the prognosis.
- category: Urologic
  name: Bladder and Bowel Dysfunction
  description: >
    Detrusor overactivity, urgency, voiding postponement and constipation.
    Modelled here as a co-occurring modifier: it raises infection risk despite
    prophylaxis, roughly halves the spontaneous-resolution rate and lowers
    surgical success.
  phenotype_term:
    preferred_term: Functional abnormality of the bladder
    term:
      id: HP:0000009
      label: Functional abnormality of the bladder
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with VUR with bladder or bowel dysfunction are at a higher risk of developing infections despite continuous prophylaxis and have a much lower rate of spontaneous resolution (31% compared to 61%) and reduced success rates after endoscopic VUR surgical procedures."
    explanation: Quantifies the modifying effect of bladder-bowel dysfunction.
- category: Musculoskeletal
  name: Joint Hypermobility
  description: >
    Generalised joint hypermobility accompanies TNXB-related familial VUR
    (VUR8), reflecting the extracellular-matrix role of tenascin X; it has been
    proposed as a non-invasive clinical clue to a TNXB aetiology.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  subtype: VUR8
  evidence:
  - reference: PMID:26408188
    reference_title: "Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all the individuals with the TNXB variants who had joint mobility examination done have significant joint hypermobility as assessed by Beighton score"
    explanation: >
      Documents joint hypermobility in TNXB-variant carriers with primary VUR.

genetic:
- name: ROBO2
  gene_term:
    preferred_term: ROBO2
    term:
      id: hgnc:10250
      label: ROBO2
  relationship_type: CAUSATIVE
  subtype: VUR2
  presence: PRESENT
  notes: >
    ROBO2 encodes the receptor for SLIT ligands; SLIT2-ROBO2 signalling
    restricts the domain of GDNF expression in the metanephric mesenchyme and so
    positions the ureteric bud. Truncating/dominant-negative and intracellular
    missense alleles are reported.
  evidence:
  - reference: PMID:17357069
    reference_title: "Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families."
    explanation: Familial segregation of ROBO2 variants with VUR.
  - reference: PMID:26408188
    reference_title: "Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, familial PVUR is due to rare variants in TNXB and ROBO2 in 12% of all families with familial PVUR studied in this cohort."
    explanation: >
      Quantifies the combined TNXB/ROBO2 yield in a familial primary-VUR cohort.
  - reference: PMID:19959718
    reference_title: "Whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We tested for but did not detect association with six candidate genes (AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A)."
    explanation: >
      Scope limit: ROBO2 is a rare-variant cause in individual families, but
      common ROBO2 variation showed no association with VUR in a large
      case-control and family-based analysis.
- name: SOX17
  gene_term:
    preferred_term: SOX17
    term:
      id: hgnc:18122
      label: SOX17
  relationship_type: CAUSATIVE
  subtype: VUR3
  presence: PRESENT
  notes: >
    The recurrent p.Y259N allele is not loss-of-function but accumulates,
    producing excessive antagonism of Wnt/beta-catenin signalling during renal
    and urinary tract development. The evidence base is thin — a single 2010
    series of eight CAKUT patients — and a later screen of familial primary-VUR
    families found only one SOX17 variant of uncertain significance, so the
    CAUSATIVE designation reflects the OMIM/MONDO VUR3 series assignment rather
    than a large replicated dataset.
  evidence:
  - reference: PMID:20960469
    reference_title: "Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One mutation, c.775T>A (p.Y259N), recurred in six patients."
    explanation: Recurrent SOX17 allele in CAKUT/VUR patients.
  - reference: PMID:20960469
    reference_title: "Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection studies indicated a 5-10-fold increase in the levels of the mutant protein relative to wild-type SOX17 in transfected kidney cells."
    explanation: >
      Functional data showing the mutant protein accumulates, the proposed
      mechanism of excess Wnt antagonism.
- name: TNXB
  gene_term:
    preferred_term: TNXB
    term:
      id: hgnc:11976
      label: TNXB
  relationship_type: CAUSATIVE
  subtype: VUR8
  presence: PRESENT
  notes: >
    Tenascin XB is a large extracellular matrix glycoprotein expressed in the
    developing ureterovesical junction. Heterozygous rare missense variants
    cluster in the fibronectin III domains. TNXB carriers had an elevated hazard
    of progression to kidney failure in a Chinese national registry, but with
    only three carriers and a very wide confidence interval (HR 20.3, 95% CI
    2.4-168.7) the point estimate should not be taken at face value.
  evidence:
  - reference: PMID:23620400
    reference_title: "TNXB mutations can cause vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation segregated with disease in the affected family as well as with a pathogenic G1331R change in another family."
    explanation: Segregation of TNXB variants with familial VUR in two families.
  - reference: PMID:34059960
    reference_title: "Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAX2 mutation carriers (HR 5.1, 95% CI 1.3-20.0; P = 0.02) and TNXB mutation carriers (HR 20.3, 95% CI 2.4-168.7; P = 0.01) were associated with increased risk of progression to ESRD."
    explanation: >
      Establishes TNXB genotype as a prognostic factor for kidney failure in
      primary VUR.
- name: SLIT2
  gene_term:
    preferred_term: SLIT2
    term:
      id: hgnc:11086
      label: SLIT2
  relationship_type: CAUSATIVE
  presence: PRESENT
  notes: >
    The ligand partner of ROBO2. Not assigned its own VUR locus number, but
    SLIT2 was among the recurrent monogenic causes in a national primary-VUR
    exome registry, consistent with the SLIT-ROBO budding-position mechanism.
  evidence:
  - reference: PMID:34059960
    reference_title: "Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These genes included PAX2 (n = 4), TNXB (n = 3), GATA3 (n = 3), SLIT2 (n = 3), ROBO2 (n = 2), TBX18 (n = 2), and the other 11 genes (one gene for each patient)."
    explanation: >
      SLIT2 among the recurrently mutated genes in an exome-sequenced
      primary-VUR cohort.
- name: Monogenic diagnostic yield in primary VUR
  relationship_type: SUSCEPTIBILITY
  presence: PRESENT
  notes: >
    Even with exome sequencing, a monogenic cause is found in only a small
    minority of primary VUR, and in familial cohorts most families remain
    unexplained. This is the quantitative statement of locus heterogeneity that
    motivates the VUR1-VUR8 linkage series.
  evidence:
  - reference: PMID:34059960
    reference_title: "Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A monogenic cause was identified in 28 patients (7.39%)."
    explanation: Diagnostic yield of exome sequencing in unselected primary VUR.
  - reference: PMID:26408188
    reference_title: "Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We did not find any possible disease-causing variants in >80% of individuals with familial PVUR, thus further confirming that PVUR is genetically heterogeneous."
    explanation: >
      Most familial primary VUR remains molecularly unexplained even after
      targeted sequencing.

diagnosis:
- name: Voiding Cystourethrography (VCUG)
  description: >
    Direct contrast cystography during voiding is the diagnostic gold standard;
    it demonstrates reflux, allows International Reflux Study grading (I-V), and
    shows associated anatomy (duplication, diverticula, urethral abnormalities).
  diagnosis_term:
    preferred_term: voiding cystourethrography
    term:
      id: NCIT:C38049
      label: Cystography
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the gold standard for evaluating VUR is direct cystography with voiding cystourethrogram (VCUG)"
    explanation: Establishes VCUG as the reference diagnostic test.
- name: Renal Ultrasonography
  description: >
    First-line imaging for renal anatomy, cortical thickness and hydronephrosis;
    it cannot however exclude high-grade reflux.
  diagnosis_term:
    preferred_term: renal ultrasound
    term:
      id: NCIT:C159885
      label: Renal Ultrasound
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unfortunately, ultrasound lacks high sensitivity or specificity for detecting high-grade VUR."
    explanation: >
      Defines the role and the limitation of ultrasound in the VUR diagnostic
      pathway.
- name: Sibling and Offspring Screening
  description: >
    Because of the high familial recurrence, baseline renal ultrasound is
    recommended for siblings of an affected child, particularly those aged 3 or
    younger, with VCUG reserved for those with an abnormal ultrasound or a UTI.
    Routine screening of asymptomatic siblings with a normal ultrasound is not
    currently recommended.
  diagnosis_term:
    preferred_term: renal ultrasound
    term:
      id: NCIT:C159885
      label: Renal Ultrasound
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Baseline ultrasound imaging for siblings of patients with VUR is recommended, as their incidence of VUR is reported to be between 27% and 46%, particularly in those children aged 3 or younger."
    explanation: >
      Supports the family-screening recommendation that follows from the
      familial nature of the disease.
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Among siblings, the incidence of VUR is about 30%, although routine screening of asymptomatic siblings with normal renal ultrasound examinations is presently not recommended."
    explanation: >
      Documents the limit of the screening recommendation; hence PARTIAL.

progression:
- phase: Spontaneous resolution of low-grade reflux
  age_range: Birth to 5 years
  notes: >
    Primary VUR frequently resolves as the child grows and the intramural
    ureteric tunnel lengthens. About 70-80% of grade I-II reflux resolves by age
    5. This natural history is the reason management is predominantly expectant
    in infancy.
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "About 75% (70% to 80%) of children with grade I and II VUR will spontaneously resolve their VUR by age 5."
    explanation: Quantifies resolution in low-grade reflux.
- phase: Persistent high-grade or bilateral reflux
  age_range: Over 5 years
  notes: >
    Grades III-IV resolve in 60-70% over 5 years when unilateral and discovered
    before age 2, but only 10-20% in children over 5 with bilateral reflux, and
    grade V rarely resolves without surgery. These are the children in whom
    intervention is considered.
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, in children over age 5 with bilateral VUR, the rate of spontaneous resolution drops to only 10% to 20% over 5 years. For patients with grade V disease, spontaneous resolution without surgical intervention is rare."
    explanation: Quantifies the poor resolution of high-grade, bilateral reflux.
- phase: Ongoing renal scar accrual
  notes: >
    New renal scars continue to form beyond 5 years of age and can occur at any
    reflux grade, so surveillance cannot be discontinued simply on the basis of
    age or low grade.
  evidence:
  - reference: PMID:3153345
    reference_title: "Vesico-uretero-renal reflux and the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Contrary to earlier reports, a recent survey has documented that new scars in children develop with significant frequency beyond 5 years of age."
    explanation: Documents late scar accrual.

treatments:
- name: Continuous Antimicrobial Prophylaxis
  description: >
    Low-dose continuous antibiotic prophylaxis (commonly
    trimethoprim-sulfamethoxazole or nitrofurantoin) while awaiting spontaneous
    resolution. The RIVUR randomised trial showed prophylaxis halves recurrent
    UTI but did NOT reduce renal scarring over 2 years, and it substantially
    increases trimethoprim-sulfamethoxazole resistance among breakthrough
    Escherichia coli isolates — the central trade-off in VUR management.
    Prophylaxis is not indicated in children with a normal urinary tract after a
    UTI.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: continuous antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
    therapeutic_agent:
    - preferred_term: trimethoprim-sulfamethoxazole
      term:
        id: NCIT:C909
        label: Trimethoprim-Sulfamethoxazole
    - preferred_term: nitrofurantoin
      term:
        id: NCIT:C29293
        label: Nitrofurantoin
  target_mechanisms:
  - target: Ascending Infection and Acute Pyelonephritis
    treatment_effect: INHIBITS
  target_phenotypes:
  - preferred_term: Recurrent urinary tract infections
    term:
      id: HP:0000010
      label: Recurrent urinary tract infections
  evidence:
  - reference: PMID:24795142
    reference_title: "Antimicrobial prophylaxis for children with vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo"
    explanation: >
      Randomised evidence that prophylaxis roughly halves recurrent UTI in
      children with VUR (relative risk 0.55).
  - reference: PMID:24795142
    reference_title: "Antimicrobial prophylaxis for children with vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring."
    explanation: >
      Qualifies the benefit: infection prevention does not translate into
      prevention of the renal lesion, consistent with a substantial congenital
      component of reflux nephropathy.
  - reference: PMID:24795142
    reference_title: "Antimicrobial prophylaxis for children with vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group."
    explanation: >
      Documents the antimicrobial-resistance cost that qualifies the benefit of
      prophylaxis.
- name: Bladder and Bowel Dysfunction Management
  description: >
    Timed voiding, laxative treatment of constipation, pelvic floor therapy,
    behavioural modification and, where indicated, anticholinergics. Addressing
    bladder-bowel dysfunction lowers infection risk and improves spontaneous
    resolution, and should precede any consideration of anti-reflux surgery.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: behavioral counseling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  target_phenotypes:
  - preferred_term: Functional abnormality of the bladder
    term:
      id: HP:0000009
      label: Functional abnormality of the bladder
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment for bladder or bowel dysfunction, including timed voiding, laxatives, pelvic floor therapy and exercises, behavioral modifications, and anticholinergic therapy, effectively reduces voiding symptoms, improves bladder function, and increases spontaneous resolution."
    explanation: >
      Documents the components and the benefit of bladder-bowel dysfunction
      management.
- name: Ureteral Reimplantation (Anti-Reflux Surgery)
  description: >
    Open, laparoscopic or robotic ureteric reimplantation lengthens the
    intramural tunnel and restores the flap valve. It is reserved for
    breakthrough febrile infections, progressive renal damage or persistent
    high-grade reflux, and reduces the frequency of acute pyelonephritic
    episodes, though older comparative studies did not show a lower overall UTI
    recurrence rate than medical management.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: ureteral reimplantation
    term:
      id: NCIT:C101242
      label: Reimplantation
  target_mechanisms:
  - target: Ureterovesical Junction Incompetence
    treatment_effect: RESTORES
  evidence:
  - reference: PMID:3153345
    reference_title: "Vesico-uretero-renal reflux and the kidney."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Prospective studies have not shown different recurrence rates of urinary tract infections in medically managed compared with surgically managed children. The frequency of acute pyelonephritic attacks decreased significantly after operation."
    explanation: >
      Supports a specific benefit of surgery (fewer pyelonephritic attacks)
      while refuting a general reduction in UTI recurrence; hence PARTIAL.
- name: Endoscopic Subureteric Injection
  description: >
    Cystoscopic injection of a bulking agent (dextranomer/hyaluronic acid
    copolymer) under the ureteric orifice to coapt the distal ureter. It is less
    invasive than reimplantation but, per current clinical guidance, offers no
    significant advantage over antibiotic prophylaxis for preventing new UTIs or
    renal scarring in most patients and carries its own procedural risks.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: endoscopic subureteric bulking-agent injection
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    therapeutic_agent:
    - preferred_term: dextranomer/hyaluronic acid copolymer bulking agent
      term:
        id: CHEBI:16336
        label: hyaluronic acid
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, endoscopic treatment does not offer significant advantages over antibiotic prophylaxis in preventing new UTIs or renal scarring in most patients."
    explanation: >
      Qualifies the role of endoscopic treatment; it is an option rather than a
      superior therapy.
- name: Surveillance and Expectant Management
  description: >
    Because most primary VUR resolves spontaneously, the default approach in
    infants is close monitoring for UTI, renal growth and kidney damage, with
    escalation only for recurrent infection, progressive damage or inadequate
    renal growth.
  action_category: MONITORING
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Generally, the most effective approach to managing VUR in infants involves closely monitoring them for UTIs and kidney damage."
    explanation: Establishes expectant management as the default in infants.
- name: Genetic Counseling and Family Evaluation
  description: >
    Counselling should convey the high familial recurrence (roughly one third of
    siblings, up to two thirds of offspring of an affected mother), the marked
    locus heterogeneity that limits molecular diagnosis, and the resulting role
    of imaging-based rather than gene-based family evaluation.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A genetic predisposition for the disorder exists, as up to two-thirds of children born to women with primary VUR will also exhibit the condition."
    explanation: The recurrence figure that underpins family counselling.

clinical_trials:
- name: NCT00405704
  phase: PHASE_III
  status: COMPLETED
  description: >
    Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR): a
    2-year, multisite, randomized, placebo-controlled trial of
    trimethoprim-sulfamethoxazole prophylaxis in 607 children with VUR diagnosed
    after a first or second febrile or symptomatic urinary tract infection.
  target_phenotypes:
  - preferred_term: Recurrent urinary tract infections
    term:
      id: HP:0000010
      label: Recurrent urinary tract infections
  - preferred_term: Renal cortical atrophy
    term:
      id: HP:0002048
      label: Renal cortical atrophy
  evidence:
  - reference: PMID:24795142
    reference_title: "Antimicrobial prophylaxis for children with vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim-sulfamethoxazole prophylaxis in preventing recurrences (primary outcome)."
    explanation: Describes the RIVUR trial design and population.
  - reference: clinicaltrials:NCT00405704
    reference_title: "Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance."
    explanation: >
      ClinicalTrials.gov registration confirming the trial identity and its
      pre-specified secondary outcomes, including the renal-scarring endpoint
      that the trial did not meet.

differential_diagnoses:
- name: Secondary vesicoureteral reflux
  description: >
    Reflux caused by elevated intravesical pressure or an anatomically abnormal
    bladder outlet — posterior urethral valves, neurogenic bladder (spina
    bifida), bladder exstrophy, urinary outlet obstruction. Distinguished by the
    presence of the underlying obstructive or neurological lesion on cystography
    and urodynamics.
  evidence:
  - reference: PMID:33085409
    reference_title: "Vesicoureteral Reflux."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "VUR may also be associated with other congenital conditions such as posterior urethral valves, neurogenic bladder, spina bifida, urinary outlet obstruction, bladder overactivity, imperforate anus, ureterocele, and bladder exstrophy."
    explanation: Lists the conditions that produce secondary VUR.
- name: Syndromic CAKUT with vesicoureteral reflux
  description: >
    VUR as one feature of a defined multisystem disorder — renal coloboma
    syndrome (PAX2), branchio-oto-renal syndrome, urofacial (Ochoa) syndrome,
    prune belly syndrome, exstrophy-epispadias complex. Suspected when
    extrarenal features are present; extrarenal manifestations more than double
    the monogenic diagnostic yield.
  evidence:
  - reference: PMID:34059960
    reference_title: "Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was a significant difference in the rate of gene mutations between patients with or without extrarenal complications (14.1% vs. 6%, P = 0.035)."
    explanation: >
      Extrarenal features substantially raise the probability of an identifiable
      (often syndromic) monogenic cause.

discussions:
- discussion_id: vur_unidentified_locus_genes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    What genes underlie the VUR1 (1p13), VUR4 (chromosome 5), VUR5 (chromosome
    13), VUR6 (chromosome 18), VUR7 (12p11-q13) and 10q26 linkage intervals?
  attaches_to:
  - pathophysiology#Abnormal Ureteric Bud Outgrowth Position
  rationale: >
    Six of the mapped familial VUR loci still have no identified gene, and even
    resequencing of the strongest interval (10q26, ~9 Mb, 69 genes) did not
    clearly implicate a single gene. Together with the roughly 7% monogenic
    diagnostic yield of exome sequencing in unselected primary VUR and the
    finding that more than 80% of familial cases have no identifiable variant,
    this means the molecular basis of most familial VUR is unknown. Whether the
    missing signal is non-coding regulatory variation acting on ureteric bud
    positioning, structural variation, or oligogenic combinations is unresolved.
  proposed_experiments:
  - experiment_id: vur_wgs_multiplex_pedigrees
    name: Whole-genome sequencing of large multiplex VUR pedigrees
    description: >
      Sequence whole genomes (not exomes) in multigenerational familial VUR
      kindreds linked to the mapped intervals, to capture non-coding regulatory
      and structural variation missed by exome sequencing.
  - experiment_id: vur_uvj_single_cell_atlas
    name: Single-cell and spatial atlas of the developing human ureterovesical junction
    description: >
      Profile the human nephric duct and forming ureterovesical junction by
      single-cell and spatial transcriptomics to prioritise candidate genes
      expressed at the budding site within each linkage interval.
  evidence:
  - reference: PMID:29097723
    reference_title: "Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ~9Mb region contains 69 genes, including some good biological candidates. Resequencing this region in selected individuals did not clearly implicate any gene but FOXI2, FANK1 and GLRX3 remain candidates for further investigation."
    explanation: >
      Documents the unresolved state of even the strongest familial VUR linkage
      interval.
- discussion_id: vur_congenital_vs_acquired_renal_lesion
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    Can any intervention prevent the renal lesion of familial VUR, given that
    halving urinary tract infection does not reduce renal scarring?
  attaches_to:
  - pathophysiology#Renal Cortical Scarring
  - pathophysiology#Congenital Renal Hypodysplasia
  rationale: >
    RIVUR showed that continuous antimicrobial prophylaxis halves recurrent UTI
    without changing the rate of renal scarring, while carrying a clear
    resistance cost. If a substantial fraction of the renal lesion is congenital
    hypodysplasia determined at the time of ureteric bud outgrowth, then no
    postnatal infection-directed strategy can prevent it, and the appropriate
    outcome measure for VUR trials may need to change. The relative contribution
    of congenital versus acquired injury in an individual child cannot currently
    be determined at diagnosis.
  proposed_experiments:
  - experiment_id: vur_neonatal_dmsa_partition
    name: Neonatal DMSA cohort partitioning congenital from acquired renal lesions
    description: >
      Prospectively image children detected antenatally or at first UTI with
      early (neonatal) DMSA plus longitudinal follow-up imaging, to separate
      pre-existing hypodysplasia from newly acquired post-pyelonephritic scars.
  - experiment_id: vur_genotype_stratified_prophylaxis
    name: Genotype-stratified analysis of prophylaxis outcomes
    description: >
      Re-analyse or prospectively stratify prophylaxis trials by molecular
      subtype (e.g. TNXB and PAX2 carriers) to test whether genotype predicts
      response to infection-directed therapy.
  evidence:
  - reference: PMID:24795142
    reference_title: "Antimicrobial prophylaxis for children with vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively)."
    explanation: The negative scarring outcome that motivates the gap.
  - reference: PMID:16433689
    reference_title: "Vesicoureteric reflux and renal malformations: a developmental problem."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Despite treatment of affected children for the past 40 years, the incidence of end-stage renal disease secondary to VUR has not decreased."
    explanation: >
      Forty years of infection-directed treatment has not changed the
      population-level renal outcome.
- discussion_id: vur_mek_inhibition_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >
    Does pharmacological MEK/ERK inhibition during ureteric bud outgrowth, which
    prevents CAKUT in Robo2/Gen1 double-heterozygous mice, have any bearing on
    human familial VUR?
  attaches_to:
  - pathophysiology#Abnormal Ureteric Bud Outgrowth Position
  rationale: >
    Intraperitoneal U0126 given to pregnant mice prevents the CAKUT phenotype in
    Robo2(PB/+)Gen1(PB/+) offspring, identifying MAPK/ERK as a convergent
    downstream node of the budding-position defect. This is a striking
    mechanistic result, but its translational validity is unknown: the mouse
    model is engineered and digenic, the intervention is a systemic MEK
    inhibitor given during pregnancy (with obvious developmental-toxicity and
    ethical barriers), and no human VUR has been shown to be MAPK/ERK-driven. It
    is a mechanistic probe of the budding-position model rather than a
    therapeutic lead.
  proposed_experiments:
  - experiment_id: vur_erk_patient_cells
    name: ERK pathway activity in human ROBO2/SLIT2 variant carriers
    description: >
      Test whether patient-derived fibroblasts or urinary-tract organoids from
      human ROBO2 or SLIT2 variant carriers show altered ERK phosphorylation
      comparable to the mouse model.
  - experiment_id: vur_gen1_oligogenic_burden
    name: Oligogenic burden test for GEN1 and ERK-pathway modifiers
    description: >
      Determine whether GEN1 or other ERK-pathway modifier alleles contribute to
      human familial VUR in oligogenic burden analyses of multiplex cohorts.
  evidence:
  - reference: PMID:36870240
    reference_title: "Inhibition of MAPK/ERK pathway activation rescues congenital anomalies of the kidney and urinary tract (CAKUT) in Robo2(PB/+) Gen1(PB/+) mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Intraperitoneal injection of U0126 during pregnancy prevented the development of the CAKUT phenotype in Robo2PB/+Gen1PB/+ mice."
    explanation: >
      The model-system result whose translation to human familial VUR is
      unestablished.

animal_models:
- species: mouse (Mus musculus)
  genotype: Robo2 heterozygous and mosaic loss-of-function mutants
  category: Gene-dosage loss-of-function model
  genes:
  - preferred_term: ROBO2
    term:
      id: hgnc:10250
      label: ROBO2
  description: >
    Reducing Robo2 gene dosage in mice reproduces the human CAKUT-VUR phenotype,
    supplying the in vivo evidence that SLIT-ROBO signalling controls ureteric
    bud position and ureterovesical junction competence. Recapitulates the human
    VUR2 subtype.
  associated_phenotypes:
  - Vesicoureteral reflux
  - Congenital anomalies of the kidney and urinary tract
  evidence:
  - reference: PMID:17357069
    reference_title: "Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes."
    explanation: >
      Direct statement of phenotype recapitulation in the Robo2 dosage model.
- species: mouse (Mus musculus)
  genotype: Robo2(PB/+) Gen1(PB/+) digenic piggyBac insertional mutants
  category: Digenic insertional-mutagenesis model
  genes:
  - preferred_term: ROBO2
    term:
      id: hgnc:10250
      label: ROBO2
  description: >
    A digenic model in which Robo2 and Gen1 co-regulate ureteric bud germination
    through MAPK/ERK; prenatal MEK inhibition with U0126 prevents the CAKUT
    phenotype. Limitation: the model is engineered and digenic, the rescue
    requires systemic MEK inhibition during pregnancy, and no human VUR has been
    shown to be MAPK/ERK-driven, so this is a mechanistic probe rather than a
    therapeutic model (see the HUMAN_MODEL_MISMATCH discussion).
  associated_phenotypes:
  - Ectopic ureteric bud outgrowth
  - Congenital anomalies of the kidney and urinary tract
  evidence:
  - reference: PMID:36870240
    reference_title: "Inhibition of MAPK/ERK pathway activation rescues congenital anomalies of the kidney and urinary tract (CAKUT) in Robo2(PB/+) Gen1(PB/+) mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Intraperitoneal injection of U0126 during pregnancy prevented the development of the CAKUT phenotype in Robo2PB/+Gen1PB/+ mice."
    explanation: >
      Defines the model and its pharmacological rescue.
- species: mouse (Mus musculus)
  genotype: C3H/HeOuJ, an immunocompetent inbred strain with native vesicoureteral reflux, transurethrally inoculated with uropathogenic Escherichia coli
  category: Infection model on a refluxing genetic background
  description: >
    The standard experimental model of acquired reflux nephropathy: mice that
    natively have vesicoureteral reflux develop renal mucosal injury,
    tubulointerstitial nephritis and cortical fibrosis after ascending
    uropathogenic E. coli infection, with the degree of fibrosis tracking the
    degree of leukocyte recruitment rather than bacterial burden alone.
  associated_phenotypes:
  - Acute pyelonephritis
  - Tubulointerstitial nephritis
  - Renal cortical fibrosis
  evidence:
  - reference: PMID:27760770
    reference_title: "Inflammation drives renal scarring in experimental pyelonephritis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis."
    explanation: >
      Explicit statement of phenotype recapitulation against human acquired
      renal scarring.
  - reference: PMID:33148615
    reference_title: "Neutrophil-Macrophage Imbalance Drives the Development of Renal Scarring during Experimental Pyelonephritis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We used a preclinical model of uropathogenic Escherichia coli-induced acute pyelonephritis to determine the contribution of neutrophils and monocytes to resolution of the condition and the subsequent development of kidney fibrosis."
    explanation: >
      Describes the same model used to dissect the leukocyte contribution to
      scarring.

mappings:
  mondo_mappings:
  - term:
      id: MONDO:0017329
      label: familial vesicoureteral reflux
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0017329 (familial vesicoureteral reflux) is the disease term for
      this entry; the entry scope (primary, non-syndromic, familial VUR
      including the VUR1-VUR8 series and the X-linked form) matches the
      MONDO/Orphanet definition.

📚

References & Deep Research

References

2

PMID:33085409

Vesicoureteral Reflux.

No top-level findings curated for this source.

PMID:16433689

Vesicoureteric reflux and renal malformations: a developmental problem.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Addendum — resolved ontology identifiers

claude-haiku-4-5-20251001, claude-opus-5[1m] 2026-08-01T02:29:45.762283

The two OAK verification jobs I had backgrounded have now returned, so four identifiers I flagged [UNVERIFIED] in §12 and Appendix B are resolved:

Addendum — resolved ontology identifiers

CHEBI (therapeutic agents for prophylaxis)

Agent	CHEBI ID	Canonical label (verified)
Trimethoprim	CHEBI:45924	`trimethoprim`
Sulfamethoxazole	CHEBI:9332	`sulfamethoxazole`
Cephalexin	CHEBI:3534	`cephalexin` — note the label is `cephalexin`, not `cefalexin`; `CHEBI:135750` is the distinct prodrug cefalexin pivoxil
Nitrofurantoin	CHEBI:71415	`nitrofurantoin` (already verified)
Amoxicillin	CHEBI:2676	`amoxicillin` (already verified)

So the RIVUR/PREDICT regimen is curated as therapeutic_agent with two entries — CHEBI:45924 + CHEBI:9332 — under treatment_term: NCIT:C15986.

NCIT (treatment action terms)

NCIT:C51993 Antibiotic Prophylaxis — definition "Administration of antibiotics with the intent of preventing bacterial infection." Parent is NCIT:C15843 Preventive Intervention, which is not under NCIT:C25218 (Clinical Intervention or Procedure). This term will therefore likely fail the dismech TreatmentTerm dynamic-enum check. Use NCIT:C15986 Pharmacotherapy as treatment_term and carry the prophylactic intent in the treatment name/description.
NCIT:C101242 Reimplantation — is_a NCIT:C64982 Therapeutic Surgical Procedure, so it is reachable from NCIT:C25218 and is safe for open ureteral reimplantation (with therapeutic_modality: SURGERY).
NCIT:C15240 Genetic Counseling and NCIT:C15986 Pharmacotherapy — labels confirmed as used in §12/§13.

Everything else flagged in Appendix B remains unverified and should still be resolved before those items enter a KB entry.

Familial Vesicoureteral Reflux

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Pathophysiology

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References & Deep Research

References

Deep Research

Addendum — resolved ontology identifiers