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Pseudostratified epithelia (PSE) are a common type of columnar epithelia found in a wealth of embryonic and adult tissues such as ectodermal placodes, the trachea, the ureter, the gut and the neuroepithelium. PSE are characterized by the choreographed displacement of cells' nuclei along the apicobasal axis according to phases of their cell cycle. Such movements, called interkinetic movements (INM), have been proposed to influence tissue expansion and shape and suggested as culprit in several congenital diseases such as CAKUT (Congenital anomalies of kidney and urinary tract) and esophageal atresia. INM rely on cytoskeleton dynamics just as adhesion, contractility and mitosis do. Therefore, long term impairment of INM without affecting proliferation and adhesion is currently technically unachievable. Here we bypassed this hurdle by generating a 2D agent-based model of a proliferating PSE and compared its output to the growth of the chick neuroepithelium to assess the interplay between INM and these other important cell processes during growth of a PSE. We found that INM directly generates apical expansion and apical nuclear crowding. In addition, our data strongly suggest that apicobasal elongation of cells is not an emerging property of a proliferative PSE but rather requires a specific elongation program. We then discuss how such program might functionally link INM, tissue growth and differentiation., Competing Interests: The authors have declared that no competing interests exist.

Congenital abnormalities of the kidney and urinary tract (CAKUT) form the leading cause of pediatric end-stage renal disease. Knowledge on the molecular mechanisms that underlie CAKUT leads to the improvement of DNA diagnostics and counseling regarding prognosis and recurrence risk estimation for CAKUT patients and their relatives. Implementation of next generation sequencing in research and diagnostic settings has led to the identification of the molecular basis of many developmental diseases. In this review, we summarize the efforts on next generation sequencing in CAKUT research and we discuss how next generation sequencing added to our understanding of CAKUT genetics. Although next generation sequencing has certainly proven to be a game changer in the field of disease gene identification and novel CAKUT-causing gene variants have been identified, most CAKUT cases still remain unsolved. Occurring with genetic and phenotypic heterogeneity along with incomplete penetrance, the identification of CAKUT etiology poses many challenges. We see great potential for combined -omics approaches that include next generation sequencing in the identification of CAKUT-specific biomarkers, which is necessary to optimize the care for CAKUT patients., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: To evaluate the first 100 cases of in utero myelomeningocoele (MMC) repair and urological outcomes in a prospective analysis aiming to define possible improvement in bladder function., Patients and Methods: We used a protocol consisting of a detailed medical history, urinary tract ultrasonography, voiding cystourethrography, and urodynamic evaluation. Patients were categorised into four groups: normal, high risk (overactive bladder with a detrusor leak-point pressure >40 cm H 2 O and high filling pressures also >40 cm H 2 O), incontinent, and underactivity (underactive bladder with post-void residual urine), and patients were treated accordingly., Results: We evaluated 100 patients, at a mean age of 5.8 months (median 4 months), classified as high risk in 52.6%, incontinent in 27.4%, with underactive bladder in 4.2%, and only 14.7% had a normal bladder profile. Clean intermittent catheterisation was initiated in 57.3% of the patients and anticholinergics in 52.6%. Antibiotic prophylaxis was initiated in 19.1% of the patients presenting with vesico-ureteric reflux., Conclusion: The high incidence of abnormal bladder patterns suggests little benefit of in utero MMC surgery concerning the urinary tract., (© 2018 The Authors BJU International © 2018 BJU International.)

Morphological and morphometric assessment of the elements of the ureterovesical junction in children was performed in the present study in different age groups ranging from 24 weeks of gestation to 16 years old. We tried to answer the question whether, in human ontogenesis, there is a period of anatomical predisposition to primary vesicoureteral reflux. The study included 210 urinary bladders with juxtavesical parts of the ureters that had been obtained from routine autopsies. As a result of the study, we showed that provided the pregnancy is uncomplicated there is no inherited susceptibility that would account for reducing or disturbing the development of ureterovesical junction elements. Based on the analysis of our results concerning the anatomy and morphological changes taking place in the elements of the ureterovesical junction in different age groups, one could put forward a hypothesis that anatomical predisposition to primary vesicoureteral reflux occurs in age group II, i.e. between 28 and 37 weeks of gestation. The parameters that define interrelations between elements of the ureterovesical junction and that are considered essential for normal functioning of antireflux mechanism were still observed in age group VI in our study. This suggests that these relations are not unambiguous in children with normally structured and functionally competent vesicoureteral junction., (© 2018 Anatomical Society.)

Odd-skipped related 1 (Osr1) is a transcriptional repressor that plays critical roles in maintaining the mesenchymal stem cell population within the developing kidney. Here, we report that newborn pups with a heterozygous null mutation in Osr1 exhibit a 21% incidence of vesicoureteric reflux and have hydronephrosis and urinary tract duplications. Newborn pups have a short intravesical ureter, resulting in a less competent ureterovesical junction which arises from a delay in urinary tract development. We describe a new domain of Osr1 expression in the ureteral mesenchyme and within the developing bladder in the mouse. OSR1 was sequenced in 186 children with primary vesicoureteric reflux, and 17 have single nucleotide polymorphisms. Fifteen children have a common synonymous variant, rs12329305, one child has a rare nonsynonymous variant, rs3440471, and one child has a rare 5'-UTR variant, rs45535040 The impact of these SNPs is not clear; therefore, the role of OSR1 in human disease remains to be elucidated. Osr1 is a candidate gene implicated in the pathogenesis of vesicoureteric reflux and congenital abnormalities of the kidney and urinary tract in mice., (Copyright © 2017 the American Physiological Society.)

Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.

Although the diagnosis of vesicoureteral reflux and of reflux nephropathy is a well-established and shared procedure, its treatment nowadays is still very controversial. New developments on the knowledge of pathophysiology of renal damage associated to reflux opened the way towards a different diagnostic work-up and different therapeutic approaches. Recently, the "top-down" diagnostic approach has gained wider interest, versus the "down-top" protocol. The attention has recently focused on the renal parenchyma damage and less interest has been given to the presence and the radiological degree of vesicoureteral reflux. The review criteria were based on an in-depth search of references conducted on PubMed, using the terms "vesicoureteral reflux", "children", "incidence", "etiology", "diagnosis", "treatment" and "outcomes". The selection of the papers cited in this review was influenced by the content and the relevance to the points focused in the article.Conservative approaches include no treatment option with watchful waiting, long-term antibiotic prophylaxis and bladder rehabilitation. The operative treatment consists of endoscopic, open, laparoscopic and robotic procedures to stop the refluxing ureter.No final consensus has been achieved in literature yet, and further studies are necessary in order to better define the subset of children at risk of developing progression of renal damage.This review aims to clarify the diagnostic management and the urological-nephrological treatment of reflux in pediatric age, on the basis of a review of the best-published evidence.

Objective: To investigate the gestational age-specific outcomes and the different etiologies of megacystis diagnosed at screening ultrasound., Methods: A retrospective single-center study was conducted between 1989 and 2009. We identified all consecutive cases of megacystis prenatally diagnosed during routine ultrasound screening. Outcome, final diagnosis, and renal function were recorded., Results: Eighty-four patients were included. An isolated lower urinary tract obstruction was observed in 38/84 (45.2%), ureterovesical reflux in 9/84 (10.7%), an associated congenital abnormality in 32/84 (38.1%) and a normal bladder in 5/84 (6%). Increased gestational age at diagnosis was correlated with an increased rate of live born children (P < 0.01). No cases of megacystis diagnosed in the first trimester were born alive. When diagnosis of posterior urethral valves (PUV) was made in the third trimester, the ultimate survival rate was 11/13 (84.6%) compared with 3/12 (25%) for a diagnosis made in the second trimester (P = 0.02)., Conclusion: Lower urinary tract obstruction is the main etiology of megacystis. Megacystis can also be part of more complex malformations. Outcome of megacystis detected in the first trimester is poor. PUV detected in the third trimester had a better overall survival rate than PUV detected in the second trimester., (© 2013 John Wiley & Sons, Ltd.)

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. This disease group includes a spectrum of urinary tract defects including vesicoureteral reflux, duplex kidneys and other developmental defects that can be found alone or in combination. To identify new regulators of CAKUT, we tested the genetic cooperativity between several key regulators of urogenital system development in mice. We found a high incidence of urinary tract anomalies in Pax2;Emx2 compound heterozygous mice that are not found in single heterozygous mice. Pax2⁺/⁻;Emx2⁺/⁻ mice harbor duplex systems associated with urinary tract obstruction, bifid ureter and a high penetrance of vesicoureteral reflux. Remarkably, most compound heterozygous mice refluxed at low intravesical pressure. Early analysis of Pax2⁺/⁻;Emx2⁺/⁻ embryos point to ureter budding defects as the primary cause of urinary tract anomalies. We additionally establish Pax2 as a direct regulator of Emx2 expression in the Wolffian duct. Together, these results identify a haploinsufficient genetic combination resulting in CAKUT-like phenotype, including a high sensitivity to vesicoureteral reflux. As both genes are located on human chromosome 10q, which is lost in a proportion of VUR patients, these findings may help understand VUR and CAKUT in humans.

Antenatal hydronephrosis and vesicoureteral reflux (VUR) are common renal tract birth defects. We recently showed that disruption of the Robo2 gene is associated with VUR in humans and antenatal hydronephrosis in knockout mice. However, the natural history, causal relationship and developmental origins of these clinical conditions remain largely unclear. Although the hydronephrosis phenotype in Robo2 knockout mice has been attributed to the coexistence of ureteral reflux and obstruction in the same mice, this hypothesis has not been tested experimentally. Here we used noninvasive high-resolution micro-ultrasonography and pathological analysis to follow the progression of antenatal hydronephrosis in individual Robo2-deficient mice from embryo to adulthood. We found that hydronephrosis progressed continuously after birth with no spontaneous resolution. With the use of a microbubble ultrasound contrast agent and ultrasound-guided percutaneous aspiration, we demonstrated that antenatal hydronephrosis in Robo2-deficient mice is caused by high-grade VUR resulting from a dilated and incompetent ureterovesical junction rather than ureteral obstruction. We further documented Robo2 expression around the developing ureterovesical junction and identified early dilatation of ureteral orifice structures as a potential fetal origin of antenatal hydronephrosis and VUR. Our results thus demonstrate that Robo2 is crucial for the formation of a normal ureteral orifice and for the maintenance of an effective anti-reflux mechanism. This study also establishes a reproducible genetic mouse model of progressive antenatal hydronephrosis and primary high-grade VUR.

Vesico-ureteric reflux is the most common congenital anomaly of the urinary tract, characterized by a defective uretero-vesical junction with retrograde urine flow from the bladder toward the kidneys. Because there is strong evidence for a genetic basis for some cases of vesico-ureteric reflux, we screened 11 inbred mouse strains for reflux and kidney size and identified one strain, C3H/HeJ, that has a 100 percent incidence of vesico-ureteric reflux with otherwise normal kidneys at birth. These mice are predisposed to reflux as a result of a defective uretero-vesical junction characterized by a short intravesical ureter. This defect results from a delay in urinary tract development initially manifested by a ureteric bud arising from a more caudal location along the mesonephric duct. In contrast, C57BL/6J mice (resistant to reflux at birth) have long intravesical ureters, normally positioned ureteric buds, and no delay in urinary tract development. Genome-wide and additional fine mapping of backcross mice, derived from C3H/HeJ and C57BL/6J crosses, identified a significant reflux susceptibility locus, Vurm1, on chromosome 12 (peak logarithm of the odds=7.39). The C3H/HeJ mouse is a model of vesico-ureteric reflux without renal malformation, and further characterization of this model will allow for the identification of a pathway important for urinary tract development, a finding that will serve as a model for the human disorder.

Background: Renal pelvis dilatation (RPD) occurs in 1% of fetuses. Severe RPD (>15 mm) is frequently associated with urinary tract pathology. For the majority with mild (5 to 9 mm) to moderate (10 to 15 mm) RPD, however, there is uncertainty about the risk of abnormalities and how much postnatal investigation is required., Study Design: Systematic review of cohort studies of fetuses with RPD < or = 15 mm and metaregression to estimate risks of postnatal RPD, obstruction, and VUR., Results: Of 506 potentially relevant papers, 18 met the inclusion criteria. Risk of postnatal RPD increased with fetal RP size and earlier gestation. Odds ratios for postnatal RPD doubled per millimeter increase in fetal RP size: At 20 wk gestation, for example, 18% of fetuses with mean RP of 6 mm were estimated to have persistent postnatal RPD, compared with 95% of fetuses with 12 mm RPD, but risks were decreased by 16% to 18% per week of presentation gestation. Estimated risks of obstruction and VUR were substantially lower, particularly in the mild group such as the 6 mm example above: obstruction 2%, VUR 4%., Conclusions: Our novel risk estimates are useful for antenatal counseling at presentation. The low frequency of obstruction/VUR in mild RPD raises questions over the most appropriate investigation of these cases but further data are required before establishing definitive postnatal management pathways. We suggest the need for a large prospective multicenter study to collect individual patient parameters/results and search for additional prognostic indicators.

Purpose: Up to 1% of prenatal ultrasounds detect renal pelvic dilatation. This dilatation is associated with vesicoureteral reflux but its clinical significance and the necessity for vesicoureteral reflux detection have been questioned. We report an evaluation of fetal renal pelvic dilatation and postnatal sonographic features with the incidence of vesicoureteral reflux., Materials and Methods: Maximum fetal renal pelvic dilatation was prospectively measured at a single center between 1990 and 2003. Dilatation 4 mm or greater at less than 33 weeks of gestation, or 7 mm or greater at more than 33 weeks was the threshold for inclusion in the study. Postnatal evaluation included ultrasound and voiding cystourethrogram. Postnatal data included vesicoureteral reflux incidence and grade, and caliceal and ureteral dilatation on ultrasound., Results: Of 215 neonates 46 (21%) had vesicoureteral reflux. Mean renal pelvic dilatation was 14.4 mm in those with reflux, which was not statistically different than the mean of 11.8 mm in 169 with a normal voiding cystourethrogram. ROC analysis revealed that fetal renal pelvic dilatation was a poor discriminator of reflux. Reflux was identified in a significantly greater number of neonates with vs without postnatal calicectasis (20% vs 9%, p <0.05). When fetal renal pelvic dilatation was combined with postnatal calicectasis, only 5% of infants with dilatation less than 10 mm and isolated renal pelvic dilatation had reflux, whereas reflux was identified in 25% with fetal renal pelvic dilatation 10 mm or greater and calicectasis (p <0.02)., Conclusions: The magnitude of fetal renal pelvic dilatation is not reliably predictive of reflux and this measure alone cannot be used to direct postnatal cystography. However, postnatal calicectasis appears to be an important predictor of vesicoureteral reflux in children with fetal renal pelvic dilatation. Expectant management can be considered in the subset of newborns with minimal dilatation (less than 10 mm) and absent calicectasis.

Objectives: The main reasons of this review are: To determine some of the embryological and genetic mechanisms of vesicoureteral reflux (VUR) and associated congenital reflux nephropathy (NR); recognize different patterns of familiar clustering and identify appropriate cases where genetic counselling and investigations might be indicated; and finally, to establish the association of these phenomena (VUR and NR)., Methods: Bibliographic search of related articles until June 2007., Results: There are two kinds of primary VUR: isolated VUR and syndromic VUR; the last one has an inherited Mendelian transmission and we know the mechanisms. Epidemiological studies seem to demonstrate that isolated VUR also presents familiar clustering and its inheritance pattern is the main object of interest in some studies; most authors support the hypothesis that VUR is genetically heterogeneous and is caused by a number of different genes acting with random environmental effects. There are lots of candidate implicated genes. The characteristics of VUR (incomplete penetrance, variability of expression, spontaneous resolution...) make difficult to configure a selection of patients subsidiary of genetic study. Despite different treatment options, the incidence of renal chronic failure secondary to VUR has not decreased. Some of the candidate genes identified regulate the position of ureteral budding, a critical step in both kidney and urinary tract development. 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. Therefore, in these cases, the association of VUR and renal failure may be caused by a genetic defect affecting the formation of the kidney and the urinary tract and not by evolution of VUR. Investigation in animals is fundamental to know more about this issue (candidate genes and VUR-NR association)., Conclusion: It is important to learn patterns of familiar clustering of isolated and syndromic VUR to offer genetic counselling if possible. For this reason, we should be screening carefully all patients suffering from VUR. It is known that limitations in actual indications of genetic study exist. Prenatal diagnosis may be realized if there is a syndromic VUR with known mutation, invariable expressivity or if clinical manifestations involve risk of death. Epidemiological data and laboratory studies may give us guidance to elicit new cases of nephropathy associated to severe VUR.

Background: Vesicoureteric reflux (VUR) is the retrograde flow of urine from the bladder into the ureters. It is the most common urological anomaly in children, and a major cause of end-stage renal failure and hypertension in both children and adults. VUR is seen in approximately 1-2% of Caucasian newborns and is frequently familial., Objective and Methods: In order to search for genetic loci involved in VUR, we performed a genome-wide linkage scan using 4710 single-nucleotide polymorphisms (SNPs) in 609 individuals from 129 Irish families with >1 affected member., Results: Nonparametric linkage (NPL) analysis of the dataset yielded moderately suggestive linkage at chromosome 2q37 (NPL(max) = 2.67, p<0.001). Analysis of a subset without any additional features, such as duplex kidneys, yielded a maximum NPL score of 4.1 (p = 0.001), reaching levels of genome-wide statistical significance. Suggestive linkage was also seen at 10q26 and 6q27, and there were several smaller peaks., Conclusion: Our results confirm the previous conclusion that VUR is genetically heterogeneous, and support the identification of several disease-associated regions indicated by smaller studies, as well as indicating new regions of interest for investigation.

Congenital anomalies of the kidney and urinary tract, as well as primary vesico-ureteric reflux (VUR) and associated renal dysplasia, are the most relevant causes of end-stage renal failure in the pediatric population. In vivo and in vitro experimental studies have allowed the identification of several genes involved both in ureteric bud branching, ureteric elongation and insertion into the bladder, and in nephrogenesis. It has been proposed that both renal and ureteral abnormalities, as well as the associated renal hypo-dysplasia, may derive from a common mechanism as the result of a dysregulation of the normal developmental program. The large homologies between mice and the human genome suggest that the same genes could be involved both in rodent and human VUR. Furthermore, epidemiological observations suggest that not only syndromic but also isolated VUR is an inherited trait. Linkage analysis for homologous mouse genes in humans, genome-wide linkage studies in multigenerational families and association studies by polymorphisms support the hypothesis that VUR is genetically heterogeneous and is caused by a number of different genes acting with random environmental effects. The present teaching paper is an overview of the embryology and genetics of primary VUR and associated congenital reflux nephropathy.

Vesicoureteric reflux (VUR) is a congenital urinary tract defect caused by the failure of the ureter to insert correctly into the bladder. It occurs in up to 1% of the general population and is associated with recurrent urinary tract infections and renal failure. Despite treatment of affected children for the past 40 years, the incidence of end-stage renal disease secondary to VUR has not decreased. Twin and family studies reveal that VUR has a genetic basis. 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. 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. Therefore, in these cases, the association of VUR and renal failure may be caused by a genetic defect affecting the formation of the kidney and the urinary tract.

Objective: To investigate the variation in the dimensions of the fetal renal pelvis in relation to the degree of bladder filling in fetuses with mild pyelectasis., Methods: Eighteen third-trimester pregnant women with mild uni- or bilateral fetal pyelectasis, defined as an anteroposterior (A-P) diameter of the renal pelvis between 5 and 10 mm, were recruited for the study. The women were examined for 2-3 h by ultrasound. The A-P and transverse dilatation of the renal pelvis and the bladder dimensions (to calculate fetal bladder volume) were measured at 2-3-min intervals. Postnatally, all infants were investigated by ultrasound at 3-4 months., Results: In 6/18 fetuses a consistent relationship between the size of the renal pelvis and bladder filling was found, with a mean difference in renal pelvic diameter before and after voiding of 6.7 mm and a largest observed difference of 14.3 mm. In 12/18 fetuses no such relationship was found. Postnatally, five infants were referred to a pediatric urologist. The investigations in these five infants could not confirm the hypothesis that variation in renal pelvic size in relation to bladder size may predict prenatal vesicoureteric reflux (VUR)., Conclusions: In mild pyelectasis the size of the renal pelvis is highly variable in one-third of cases. The association with bladder volume and micturition suggests evidence of VUR, but this could not be proven. If cut-off values are used to differentiate between normal and abnormal renal pelvic size then not only gestational age but also the degree of bladder filling at the time of measurement should be taken into account. Caution should be expressed when the diagnosis of a possible urological anomaly is based on a single measurement during just one investigation.

RET, a tyrosine kinase receptor essential for kidney development, has recently been shown to be important for the formation of the urinary tract. When RET is overexpressed in the HoxB7/Ret transgenic mouse, kidneys are small and cystic, and in some of the mice, the ureters are grossly dilated. Here, we report that the observed ureteral dilatation is associated with the urinary tract abnormality vesicoureteric reflux (VUR), in which urine flows retrogradely from the bladder to the ureter. Reflux was determined in vitro by injecting methylene blue into the bladders of HoxB7/Ret and wild-type mice. At postnatal day 1, 30% of HoxB7/Ret mice had VUR compared with 4% of wild-type mice (P < 0.05). The length of the intravesical ureteral tunnel was shorter in HoxB7/Ret mice compared with wild-type mice, on both the right and the left sides (P < 0.05), suggesting a basis for the higher incidence of VUR in these mutants. At embryonic day 11, the ureteric bud was found to exit more caudally from the mesonephric duct in HoxB7/Ret mice, and this may predispose them to VUR (P < 0.05). Wild-type and HoxB7/Ret mice were tested for reflux at embryonic day 17, and both showed a high frequency of VUR (59 and 75%, respectively). These results suggest that VUR may occur transiently during normal urinary tract development before the ureter has completed its insertion into the bladder. In the HoxB7/Ret mouse, overexpression of RET appears to delay the maturation of the distal ureter, resulting in postnatal VUR. The HoxB7/Ret mouse is thus an important model in which to examine how vesicoureteric reflux arises during urinary tract development.

Objectives: To evaluate the severity, laterality, and gender distribution of infant vesicoureteral reflux (VUR) and its potential impact on renal outcome, we compared patients presenting fetally (FDR group) and those presenting with a urinary tract infection (INF group)., Methods: A retrospective review of 202 patients with the diagnosis of VUR before 6 months of age was performed. The grade of VUR, gender, laterality, initial renal scarring, breakthrough urinary tract infections, new renal scarring, and surgical intervention were compared between the INF group (n = 146) and FDR group (n = 56)., Results: The male/female ratio in the FDR group was 1.67:1 compared with 0.60:1 in the INF group. The FDR group had more unilateral VUR than the INF group (P <0.001), and no significant difference was found between the two groups in terms of VUR grade distribution (P = 0.13), percentage of initial damage (28% of FDR patients versus 23% of INF patients), or clinical course. In either group, boys and girls exhibited a very similar distribution of grade and renal damage., Conclusions: Our findings do not support the commonly held belief that fetally diagnosed reflux is an overwhelmingly male, bilateral, and high-grade phenomenon. Few differences were observed between infants diagnosed fetally and those diagnosed subsequent to urinary tract infection. Once diagnosed, from either group, infant reflux has neither great morbidity nor a frequent need for surgery.

Purpose: Infants with history of antenatal hydronephrosis and neonatal vesicoureteral reflux may have detectable changes in renal scans before the advent of urinary tract infection. In cases of bilateral high-grade vesicoureteral reflux, differential renal function on renal scan may not reveal renal hypoplasia since comparison of relative function may be made between two abnormal kidneys. We tested the hypothesis that ultrasonography in the neonatal period may be accurate and complementary to renal scan in detecting renal hypoplasia at birth., Materials and Methods: Twenty-six infants who presented in the antenatal period with history of hydronephrosis and were noted to have neonatal vesicoureteral reflux postnatally were studied retrospectively. They had all been treated by a prospective protocol that included renal ultrasound and renal scans in the first 6 weeks of life. All had been placed on prophylactic antibiotics and had no urinary tract infection. Multiple sonographic parameters were analyzed including kidney length, echogenicity, calyceal blunting, parenchymal thinning and focal scars. We correlated the renal morphology on ultrasound, the renal function on renal scan and the degree of reflux seen on VCUG., Results: VCUG showed reflux in 44 renal units, grade of reflux was: I (2), II (7), III (12), IV (8), and V (15). A variety of nucleides were used including DMSA in 15, DTPA in 6 and MAGIII in 5. Renal scans identified global hypoplasia without focal scars (differential function less than 40%) in 10 of 44 refluxing renal units grades I (1), III (2), IV (4), and V (3). The sonographic finding of decreased renal length (<50th percentile for age) was present in 14 refluxing units of 44 refluxing renal units, grade I (1), grade III (4 bilaterally in 1), grade IV (4 bilaterally in 1), and grade V (5 bilaterally in 2). The sonographic finding of decreased renal length (<50th percentile) correlated strongly with renal hypoplasia on renal scans in refluxing renal units (p value <.005, sensitivity 80% and specificity 82%, positive predictive value 57%, and negative predictive value 93%)., Conclusion: Postnatal ultrasonography is a reliable measure of gross renal parenchyma, and in the presence of vesicoureteral reflux correlates with renal scintilligraphy. In addition, for cases of bilateral neonatal vesicoureteral reflux, ultrasound and renal scan are complimentary, each being able to detect the abnormalities that might be missed by the other.

Objective: To develop a surgical protocol to induce vesico-ureteric reflux (VUR) in utero by ablating the ureteric tunnel in a fetal pig model., Materials and Methods: Fetal surgery was conducted on nine sows, which were divided into three groups according to changes in the surgical protocol. Sows in groups 2 and 3 received different anaesthetics and antibiotics, and the operating theatre temperature was increased. In all cases, the intramural part of the ureter was unroofed in the fetuses, which were then returned to the uterus. Upon delivery, cystograms were taken in the male piglets, and the urinary tracts removed for anatomical and histological examination., Results: All three sows in group 1 delivered healthy piglets, but the fetuses that had undergone surgery were mummified. In group 2 the animals survived the fetal intervention, as shown by ultrasonography after surgery, but the four sows aborted spontaneously within a week. In group 3, both sows delivered normally developed piglets, three of which had undergone ablation of the ureteric tunnel. VUR was present only in those renal units in which the ureteric tunnel was ablated, and this was associated with hydronephrosis, dilatation of the ureters and thinning of the renal parenchyma on gross pathological examination., Conclusions: The fetal pig model of VUR not only appears to be feasible, but with similarities in renal anatomy and physiology also seems to be ideal for investigating fetal VUR.

The understanding of vesicoureteric reflux (VUR) continues to improve, particularly as the renal tract can now be assessed prenatally. To further study the evolution of fetal renal changes, we studied two neonatal piglets that had undergone midgestation ureteric tunnel ablation. Dilatation of the pelvicalyceal system was seen radiologically and macroscopically in all three kidneys into which VUR had been created. Despite the study being marred by poor fetal survival, the results indicate that the model should be developed further to explore what appears to be an interrelationship between VUR and renal parenchymal changes in utero.

Objective: To present further arguments supporting a transient urethral obstruction occurring during early fetal development as an explanation of the origin of vesico-ureteric reflux (VUR) in baby boys., Patients and Methods: The findings of ultrasonography and voiding cysto-urethrography (VCUG) in 25 baby boys with VUR were reviewed, studying mainly bladder and urethral anomalies on VCUG and bladder-wall thickness on ultrasonography., Results: A bladder or urethral anomaly was found in 15 patients, comprising isolated posterior urethral dilatation in five, posterior urethral dilatation with a bladder anomaly in four, tubular appearance of the urethra in two and bladder neck hypercontractility with diverticulae in four. Bladder-wall thickness ranged from 1 to 8 mm (mean 3.7) and in eight patients, the thickness exceeded 5 mm., Conclusion: The bladder and urethral anomalies found in this series of patients with neonatal VUR could be explained by a transient bladder outlet obstruction that possibly occurred in utero. These findings support the theory that a significant number of cases of VUR seen in baby boys result from a transient fetal urethral obstruction.

In the absence of firmly established views on the development of nephropathy, we describe in this paper the embryogenetic and clinical aspects of kidney disease. Congenital reductive nephropathy always arises in the ureteral bud and is determined by two factors, endogenous dysplasia and endogenous obstruction. The nine well-known patterns of disease that may result are described herein. The most important starting points are as follows: (a) A dysplastically disorganized and hence refluxive trigone of the bladder induces, via pyramidal-medullary deficiencies, a defect of the metanephros and thus what we term reflux nephropathy (III-V). BU and PN may supervene postnatally. (b) Similarly, obstruction of the ureteral outlet in the first trimester induces dysplastic ascending nephropathy. (c) The same obstruction beginning in the second trimester induces nondysplastic, purely obstructive nephropathy, characterized by glomerular hypogenesis and hemo-obliterative cirrhosis which varies considerably from stage to stage and from case to case and may go as far as complete loss of the parenchyma. (d) Obstruction of the pyeloureteral junction, occurring late in the embryonic phase and originating outside the urinary system, provides the clearest example of fully developed nondysplastic reductive nephropathy. The lesional process may come to a halt at any time. (e) Coincidence of early embryonic dysplastic-refluxive nephropathy and late embryonic infravesical obstruction (with no causal link) accounts for half the morbidity from valvular disease. The other half results from simple nondysplastic obstruction.

Twenty neonates with myelodysplasia were prospectively evaluated during the first month of life with urodynamic studies, contrast voiding cystourethrograms (VCUG) and renal ultrasound scans. Ten of 20 infants had abnormal VCUGs--6 with vesicoureteric reflux (VUR) and 4 with bladder trabeculation alone. Only 2/20 neonates had abnormal ultrasounds--both with hydroureteronephrosis secondary to VUR. Elevated leak point pressure (LPP) and/or detrusor sphincter dyssynergia (DSD) were present in 10/20 infants--6 with elevated LPP and DSD, 3 with elevated LPP alone and 1 with DSD alone. Eight of 10 neonates with DSD or elevated LPP had abnormal VCUGs--4 with VUR and 4 with bladder trabeculation alone. Conversely, 8/10 neonates without DSD or elevated LPP had normal VCUGs. Contrast VCUG performed shortly after birth, therefore, is essential for the discovery of bladder trabeculation and reflux. There is a strong correlation between an abnormal VCUG and the presence of DSD and elevated LPP, suggesting that neurogenic bladder dysfunction in utero can lead to these structural abnormalities.

A hypothesis for the embryogenesis of lower ureteral anomalies invokes variations in location and number of ureteral buds on the mesonephric duct. Such vagaries determine the length of the common nephric duct and the time of meeting of the ureteral bud (or buds) with the urogenital sinus. These factors in turn affect the density of the mesenchymal tissue and its mass in relation to the adjoining structures and, ultimately, the musculature of the trigone as well as the level of the ureteral hiatus and the musculature of the bladder base. Primary reflux, ureteral ectopy, ureteral duplication, ureterocele, functional ureteral obstruction, and congenital strictures are viewed and possibly explained in the light of the embryonal variations mentioned.

Extensive gross, microscopic and clinical studies of various ureteral anomalies have enabled investigators to set forth theories regarding the aetiologies of these anomalies consistent with observed fact. Synthesis of these observations allows for a simplified classification of mega-ureter (primary obstructed, reflux and non-obstructed, non-reflux mega-ureters), ureterocele, duplex ureters and ectopic ureters based upon some combination of mesenchymal differentiation anomalies and location anomalies. A defect early in mesenchymal differentiation would be expected to result in panureteral disease. A defect later in development would result in a focal abnormality anywhere along the course of the ureter. Influence upon ureteral bud mesenchyme by local expansion factors in the bladder base may result in various types of ureterocele. Position of the ureteral orifice on the trigone or in Wolffian duct derivatives would occur in accordance with the Weigert-Meyer principle and would correlate with upper tract dysplasias. Thus, an attempt has been made to systematize and trace the origins of mega-ureter, ureterocele, duplex ureters and ectopic ureters to defects of differentiation of the basic mesoblastic cell in aberrant locations of the ureteral bud.

Primary vesico-ureteric reflux must be graded according to severity. Significant reflux up a dilated ureter appears to be an important factor in causing renal damage. There is evidence in favour of the theory that the renal deterioration seen in some cases of reflux can be explained on a congenital basis of site or origin of the ureteral bud and resultant dysplasia of the developing kidney. Surgery should be reserved for selected patients with significant reflux.

The development and incorporation of the ureteric bud into the developing bladder is a complex process, and it is influenced by events occurring at the same time in the development of other systems in the perineum. Knowledge of the embryology of the ureteric bud and associated wolffian duct is the key to understanding the development of the entire genitourinary system. If the normal embryology is understood, the dysembryogenesis that results in many of the common anomalies of the lower urinary system is simplified. Many of the concepts proposed in this discussion are well substantiated, others are more difficult to prove conclusively. It is believed, however, that the embryologic approach provides a simplified understanding of many of the common problems encountered in pediatric urology. The key in clinical practice to the diagnosis and understanding of these defects is the cystoscopic examination. Careful assessment of the orifice's position, appearance, and tunnel length will allow the interpretation of how the abnormality came about, and also provides valuable information concerning the state of the associated renal segment. This in turn allow better therapeutic management of the problem based on the knowledge of the severity of the renal anomaly associated with the abnormality found in the bladder.

The authors sought to determine what links existed between foetal vesico-ureteric reflux and renal dysplasia. Using sheep with operation upon the foetuses in utero, at a fairly early stage of gestation, the following were obtained: 1) Foetal vesico-ureteric reflux by unilateral excision of a ureteric meatus. 2) Stenosis of the foetal ureter by ligation. In the first case, no renal dysplasia occurred. In the second case, dysplasia-type parenchymatous lesions were found. This led them to conclude that the direct relationship between isolated foetal vesico ureteric reflux created experimentally in a normal ureter (without any additional functional or organic obstructive factor) and renal dysplasia could not be demonstrated in the sheep foetus.

The tightness of the ureterovesical junction depends on all the structures composing the terminal and intra-mural ureter. The muscular, collagenic, and elastic fibers of the ureter constitute a mesh net which is stretched during bladder distention and closes the ureteric orifice as a valve. Congenital vesico-ureteric reflux results from a primary structural insufficiency of the terminal ureter or insufficiency of the bladder wall backing. As embryology shows primary reflux can be caused by a high ectopic implantation of the ureter. It results from the development of an ureteric bud appearing in a lower than normal position on the Wolffian duct. This results in a higher and more lateral opening of the ureteric orifice in the bladder which leads to a shorter intra-mural tunnel predisposing it to reflux. Secondary or acquired refluxes are associated with chronic obstructions (i.e. neurogenic bladder--lower urinary tract obstruction), and inflammatory lesions. Their pathogeneses are described and discussed. The maturation of the ureterovesical junction is considered a mechanism involving a reduced likelihood of secondary reflux. It may also, during the first years of life, palliate some minimal structural deficiencies of the intra-mural ureter, but growth and development are unlikely to normalize an ureter presenting at birth with a severe constitutional anomaly.

The ureterovesical junctions in human fetuses from 11 to 27 weeks of age were studied histologically. Anatomical relationships and origins of the periureteral sheaths, intravesical ureteral muscles, and trigonal muscles were shown. The superficial periureteral sheath arising from the vesical wall was not the source of the trigonal muscles; the deep periureteral sheath arising from the intravesical ureteral wall formed the deep trigonal muscles. The muscles of the intravesical ureter were differentiated longitudinally and formed the superficial trigonal muscles. The development of the two trigonal muscles--superficial and deep--depends on the development of the deep periureteral sheath and the intravesical ureteral muscles. From the finding that both trigonal muscles are present in fetuses compared with both periureteral sheaths or intravesical ureteral muscles in the latest stage, the ability to maintain the valve mechanism in the ureterovesical junction in the human fetus is based on the periureteral sheaths and intravesical ureter--not on the trigone.