Introduction
-
differential renal function deterioration (differential function of <40% or a fall of >10% on serial MAG3 renograms)
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significant hydronephrosis with a renal pelvis anteroposterior diameter of >3 cm on ultrasound scan
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increasing hydronephrosis with an increasing anteroposterior diameter on serial ultrasound scan
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symptomatic children.
Anatomy of the upper urinary tract
Embryology of the ureter and PUJ
Protein | Full protein name | Function | Reference |
---|---|---|---|
SHH | Sonic hedgehog | Morphogen which stimulates peri-urothelial mesenchymal cell proliferation and regulates timing of smooth muscle cell differentiation | [21] |
PTCH1 receptor | Protein patched homolog 1 | Receptor for SHH, functions as tumour suppressor when unbound | [21] |
BMP4 | Bone morphogenetic protein 4 | Growth factor, necessary for smooth muscle cell differentiation and ureter morphogenesis | [22] |
TSHZ3 | Teashirt zinc finger homeobox 3 | Transcription factor-like protein necessary for myocardin expression and ureteric smooth muscle cell differentiation | [23] |
MYOCD | Myocardin | Transcriptional co-activator, necessary for expression of contractile proteins | [23] |
TBX18 | T Box protein 18 | Transcription factor necessary for correct localisation and aggregation of smooth muscle cells around ureteric urothelium | [24] |
DLGH1 | Disks large homolog 1 | Scaffolding protein, regulates smooth muscle cell orientation | [25] |
Pathologic features of intrinsic PUJO
Modelling PUJO to understand its molecular biology
Proposed molecular mechanisms underpinning PUJO
Neurogenic factors
Myogenic factors
Gene | Full gene name | Animal | Features and mechanism | Human | Reference |
---|---|---|---|---|---|
Ace
| Angiotensin converting enzyme |
Ace
−/− mice | Hydronephrosis, renal parenchymal atrophy | [51] | |
Adamts-1
| A disintegrin-like and metallopeptidase with thrombospondin type 1 motif, 1 |
Adamts
-1−/− mice | PUJ obstruction, increased collagen at PUJ. Other urogenital anomalies. | [52] | |
Agt
| Angiotensin |
Agt
−/− mice | Hydronephrosis, renal parenchymal atrophy, | [53] | |
Agtr 1a/b
| Angiotensin II receptor type 1 (1a and 1b) |
Agtr1
−/− (1a and 1b) mice | Hydronephrosis in older mice, renal parenchymal atrophy, failure of renal pelvis development, ureteric smooth muscle hypoplasia and abnormal peristalsis | [31] | |
Aqp2
| Aquaporin 2 |
Aqp
2S256L/S256L CPH mice | Mutation in CPH mice prevents Aqp2 phosphorylation and normal trafficking. Hydronephrosis secondary to polyuria | [54] | |
Calcineurin
| Calcineurin. Also known as Protein phosphatase 3 (ppp3) |
Pax3-Cre
T/+; Cnb1
flox/ flox mice | Calcineurin inactivation in metanephric and ureteral mesenchyme giving hydronephrosis, abnormal pyeloureteral peristalsis with defective renal pelvis and smooth muscle development | [30] | |
Id2
| Inhibitor of DNA binding 2 |
Id2
−/− and Id2
+/− mice | Hydronephrosis and PUJ development | [38] | |
Nfia
| Nuclear factor I/A |
Nfia
+/− and Nfia
−/− mice | Hydroureteronephrosis, VUR, abnormal PUJ and VUJ development. CNS malformations. |
Nfia
+/−due to chromosomal translocation and deletion. VUR and CNS malformations. | [55] |
TBX18
| T-box transcription factor |
Tbx18
−/− mice | Hydroureteronephrosis, short ureters, ureteric smooth muscle defects due to abnormal smooth muscle cell differentiation and localisation | Hispanic family with autosomal dominant CAKUT predominantly PUJO. Heterozygous truncating mutation (c.1010delG) of Tbx18
| |
Tshz2 and 3
| Teashirt zinc finger family member 2 and 3 |
Tshz3
−/− mice | Hydronephrosis with PUJ configuration, abnormal smooth muscle differentiation proximal ureter |
Tshz2/Tshz3 mutations not cause of PUJO in Albanian/Macedonian population |
Increased pressure, impeded blood supply and hypoxia
Proteina
| Action | Change/timing | Species | Reference |
---|---|---|---|---|
Angiotensin II | Vasoregulatory, proinflammatory, proapoptotic, profibrotic | Increased 28 days Increased 1 week and 5 weeks Increased after mechanical stretch | Neonatal rat CUUO Adult rat CUUO In vitro podocytes | [63] [64] [65] |
α-SMA | Increases myofibroblast contractility/EMT marker | Increased 5 days Increased 4 days | Neonatal rat CUUO Adult mouse CUUO | [39] [66] |
Caspases | Proapoptotic | Increased 14 days Increased 1 day | Neonatal rat CUUO Adult rat CUUO | [67] [68] |
Clusterin | Cytoprotective via pro-survival autophagy | Increased 5 days | Neonatal rat CUUO | [39] |
COX-2 | Polyuria and natriuresis, anti-apoptotic, antifibrotic | Increased 24 h Increased 3 days (mRNA) | Adult rat CBUO Adult mouse CUUO | [69] [70] |
CTGF | Profibrotic | Increased 2 days (mRNA) | Adult rat CUUO | [45] |
EGF | Epithelial survival factor | Decreased 7 days (mRNA) (Undetectable expression in neonatal rat kidney before 4 days) Decreased 33 days Decreased at pyeloplasty (mean age 2 years) (mRNA) Decreased at pyeloplasty (mean age 5 years) | Neonatal rat CUUO Neonatal rat both CUUO and 5 day CUUO then release Human renal biopsy Human renal biopsy | [71] [39] [72] [73] |
ET-1 | Vasoconstrictor | Increased 2 days (mRNA) | Adult rat CUUO | [45] |
Fas-L | Proapoptotic | Increased 1 day (mRNA) | Adult rat CUUO | [68] |
HSP-70 | Antiapoptotic | Decreased 14 days | Neonatal CUUO | [67] |
ICAM-1 | Proinflammatory | Increased 3 days | Adult mouse CUUO | [74] |
Il-6 | Proinflammatory | Increased 2 days (mRNA) | Adult rat CUUO | [45] |
Integrin (β1) | Profibrotic | Increased 3 days Increased after mechanical stretch | Adult mouse CUUO In vitro proximal tubular cells | [75] [76] |
MCP-1 | Proinflammatory | Increased 12 days, no change 4 days Increased 2 days (mRNA) Increased at pyeloplasty (mean age 2 years) (mRNA) | Neonatal rat CUUO Adult rat CUUO Human renal biopsy | [77] [45] [72] |
MMP 2 and 9 | ECM degradation | Decreased 3 days | Adult mouse CUUO | [74] |
PAI-1 | Profibrotic, inhibits ECM degradation | Increased 7 days | Adult mouse CUUO | [78] |
PDGF | Profibrotic | Increased 4 days | Adult mouse CUUO | [66] |
NF-κB | Regulatory transcription factor | Increased 2 days | Adult mouse CUUO | [45] |
Nitric oxide | Vasodilator, anti-apoptotic, antifibrotic | Decreased 14 days | Neonatal rat CUUO | |
Renin | Cleaves angiotensinogen, upregulates renin–angiotensin system | Increased 3 days (mRNA) Increased 5 days Increased 14 days (mRNA) Increased 4–5 weeks Increased 24 h Increased after mechanical stretch | Neonatal rat CUUO Neonatal rat CUUO Neonatal rat CUUO Neonatal rat CUUO Adult rat CUUO In vitro proximal tubular cells | [71] [39] [63] [80] [81] [82] |
TGF-β | Proinflammatory, proapoptotic, profibrotic, stimulates EMT | Increased 1 day (mRNA) Increased 33 days Increased 3 days (mRNA) Increased at pyeloplasty (mean age 5 years) | Neonatal rat CUUO Neonatal rat both CUUO and 5 day CUUO then release Adult rat CUUO Human renal biopsy | [71] [39] [83] [73] |
TIMP-1 | Profibrotic, inhibits ECM degradation | Increased 5 days Increased 3 days | Adult rat CUUO Adult mouse CUUO | [84] [74] |
TNF-α | Proapoptotic, proinflammatory | Increased 14 days (mRNA) Increased 1 day Increased 2 days (mRNA) Increased 1 day | Neonatal rat CUUO Adult rat CUUO Adult rat CUUO Adult rat CUUO | [85] [68] [45] [68] |
VCAM-1 | Proinflammatory | Increased 3 days (mRNA) | Adult mouse CUUO | [86] |
VEGF (podocytes) | Endothelial survival factor | Increased 28 days Decreased 14 days | Neonatal PUUO Neonatal CUUO | [87] [87] |
VEGF (tubules) | Endothelial survival factor | Variable expression Decreased 14 days | Neonatal PUUO Neonatal CUUO | [87] [87] |
Vimentin | Intermediate filament protein/ EMT marker | Increased 5 days | Neonatal rat CUUO | [39] |
WT-1 | Transcriptional regulator, key role in renal development | Decreased 14 days | Neonatal rat CUUO | [85] |
Initiation of proinflammatory cytokines
Cytokines in the stenotic PUJ
Intra-renal cytokines
Inflammatory infiltrates
Profibrotic processes
Molecules PROMOTING tubulointerstitial fibrosis in ureteric obstruction | Molecules PREVENTING tubulointerstitial fibrosis in ureteric obstruction |
---|---|
Angiotensin II | EGF |
CTGF | MMP |
ICAM-1 | Nitric oxide |
Integrins | VEGF |
PAI-1 | |
PDGF | |
TGF-β | |
TIMP-1 |
Antifibrotic processes
Cellular apoptosis
Tubular function impairment
Genetic mechanistic clues in PUJO
Potential therapeutic molecular targets in PUJO
Angiotensin-converting enzyme and AT1 receptor inhibitors
Hydroxymethylglutaryl-CoA reductase inhibitors (statins)
TGF-β modulation
COX-2 inhibition
Other potential therapeutic options
Urinary biomarkers
Urinary biomarkers in animal studies
Urinary biomarkers in human studies
Urinary protein (corrected for creatinine)a
| Primary measured group | Comparators | Bladder urine protein level | Sensitivity/specificity/accuracyb
| Post-operative bladder urine (compared to pre-operative) | Ref |
---|---|---|---|---|---|---|
ALP | Pyeloplasty | CMP | Increased pre-operative | Se 91.4%/ Sp 100%/ Ac 94% | Decreased 12 months post-operative | [168] |
Angiotensinogen | Pyeloplasty | Healthy control CMP | Increased pre-operative | Se 93.3%c/ Sp 60%c
| [169] | |
B2-microglobulin | PUJO* | Healthy control | Increased | Decreased 42 months post-operative | [170] | |
B2-microglobulin | Pyeloplasty | Healthy control | No change | [171] | ||
Ca19-9 | Pyeloplasty | Healthy control CMP | Increased pre-operative | Se 76%d/Sp 85%d
| Decreased 3 months post-operative | [172] |
Ca19-9 | Pyeloplasty | Healthy control Hydrocoele/renal cyst | Increased pre-operative | Se 100%e/ Sp 82.6%e
| Decreased 3 months post-operative | [173] |
CyC | Pyeloplasty | Healthy control | No change | [171] | ||
EGF | PUJO* | Healthy control | Decreased (obstructed group only) | No change | [170] | |
EGF | Pyeloplasty | Healthy control | Decreased pre-operative | Increased | [174] | |
EGF | Pyeloplasty | Healthy control | Increased pre-operative | Se 70.4%/Sp 69.2% | Decreased 3 months and 1 year post-operative | [175] |
EGF | Pyeloplasty | Healthy control | No change | [176] | ||
ET-1 | Pyeloplasty | Healthy control VUR Renal stones | Increased pre-operative | Se 74.3%/Sp 90%/ Ac 81.5% | Decreased 12 months post-operative | [177] |
γGT | Pyeloplasty | CMP | Increased pre-operative | Se 62.9%/Sp 100%/Ac 74% | Decreased 12 months post-operative | [168] |
HO-1 | Pyeloplasty | Healthy control CMP | Increased pre-operative | Se 72.2%c/Sp 78.1%c
| Decreased 1 month post-operative | [178] |
IP-10 | Pyeloplasty | Healthy control | No change | [175] | ||
KIM-1 | Pyeloplasty | Healthy control CMP | Increased pre-operative | Se 100%c/Sp 71.4%c
| [179] | |
MCP-1 | Pyeloplasty | Healthy control | Increased pre-operative | Se 77.8%/Sp 69.2% | Decreased 3 months and 1 year post-operative | [175] |
MCP-1 | PUJO* | Healthy control | Increased | Decreased 42 months post-operative | [170] | |
MCP-1 | Pyeloplasty | Healthy control | Increased pre-operative | [174] | ||
MCP-1 | Pyeloplasty | Healthy control CMP | Increased pre-operative | Se 100%c/Sp 0%c
| Remains high 3 months post-operative | [180] |
MIP-1α | Pyeloplasty | Healthy control | Decreased pre-operative | Increased 1 year post-operative | [175] | |
NAG | Pyeloplasty | CMP | Increased pre-operative | Se 97.1%/Sp 80%/Ac 92% | Decreased 12 months post-operative | [168] |
NGAL | Pyeloplasty | Healthy control | No change | [171] | ||
NGAL | Pyeloplasty | Healthy control | Increased pre-operative | [181] | ||
NGAL | Pyeloplasty | Healthy control CMP | Increased pre-operative | Se 100%c/Sp 28.6%c
| Decreased 3 months post-operative | [179] |
OPN | Pyeloplasty | Healthy control | No change | [171] | ||
OPN | Pyeloplasty | Healthy control CMP | Increased pre-operative | Se 98.5%c/Sp 10.5%c
| Remains high 3 months post-operative | [180] |
RANTES | Pyeloplasty | Healthy control | No change | [175] | ||
TGF-β | Pyeloplasty | Healthy control | Increased pre-operative | Se 100%/Sp 80%/Ac 90.8% | Decreased 1 year post-operative | [176] |
TGF-β | Pyeloplasty | CMP | Increased pre-operative | Se 82%/Sp 86% | [182] |
Conclusions
Future perspectives and unanswered questions in PUJO
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What is the underlying aetiology of intrinsic congenital PUJO? Does this explain the variable outcome of PUJO and can this be targeted therapeutically?
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Does individual ability to relieve intra-renal pressure determine disease progression?
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Are therapies tested in animals applicable in children to limit renal injury?
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Can urinary biomarkers improve early identification and thus outcome of children requiring pyeloplasty?