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The article presents questions and answers related to the potential causes of hydroureteronephrosis in a 12-year-old boy who experiences symptoms like chronic constipation.

Objective: To evaluate whether grade 4-5 vesicoureteral reflux (VUR) can be predicted from renal ultrasound (RUS) findings and perform voiding cystourethrograms (VCUGs) only on high-risk patients.Methods: The RUS and VCUG images of infants with prenatally detected hydronephrosis admitted to our institution between 2003 and 2013 were re-evaluated. The UTI episodes were collected retrospectively from patient journals. Patients with complex urinary tract anomalies were excluded.Results: One hundred eighty, 44 female and 136 male, patients (352 renal units (RU)), 23 (30 RU) of them having grade 4-5 VUR, were included. The median age of the patients at the time of the RUS was 1.3 (0.1-3.0) months and the median follow-up time was 2.0 (0.1-11.2) years.In multivariate analysis, a visible ureter (OR 12.72; CI 5.33-32.04, p < 0.001) and shorter renal length (OR 2.67; CR 1.50-4.86, p < 0.001) in RUS predicted grade 4-5 VUR while a visible ureter predicted UTIs (OR 5.75; CI 2.59-12.66, p < 0.001).A three-grade risk score for high-grade VUR was developed based on the RUS findings and the patients were categorized into low-, intermediate-, and high-risk groups. The incidence of grade 4-5 VUR was 2.9% in the low-risk, 12.2% in the intermediate-risk, and 52.2% in the high-risk group. The sensitivity and specificity for detecting grade 4-5 VUR were 79 and 82%, respectively.Conclusions: In patients with antenatally detected hydronephrosis, a visible ureter and reduced renal length in RUS are significant risk factors for high-grade VUR. A RUS-based risk scoring would probably reduce the proportion of unnecessary VCUGs. [ABSTRACT FROM AUTHOR]

A clinical quiz about a female patient with systemic lupus erythematosus is presented.

Primary vesicoureteral reflux (VUR) is a common pediatric condition due to a developmental defect in the ureterovesical junction. The prevalence of VUR among individuals with connective tissue disorders, as well as the importance of the ureter and bladder wall musculature for the anti-reflux mechanism, suggest that defects in the extracellular matrix (ECM) within the ureterovesical junction may result in VUR. This review will discuss the function of the smooth muscle and its supporting ECM microenvironment with respect to VUR, and explore the association of VUR with mutations in ECM-related genes. [ABSTRACT FROM AUTHOR]

The collecting duct network and the urothelium of the ureter of the metanephric kidney are derived from the ureteric bud epithelium, initially an outgrowth from the caudal end of the Wolffian duct at the onset of the metanephric kidney development. The tips of the ureteric bud epithelium undergo reiterative branching morphogenesis, which generates more tips and trunks, whereas the ureteric trunks grow and differentiate into principal cells and intercalated cells of the collecting ducts that regulate body water and acid-base homeostasis. microRNAs (miRNAs) are a family of small non-coding RNAs that regulate a diversity of biological processes including organogenesis, mostly by negatively regulating their target gene expression. In this review, I will summarize the current knowledge on the critical roles of miRNAs expressed in the ureteric bud epithelium in ureteric bud morphogenesis and differentiation, including ureteric bud branching morphogenesis, collecting duct terminal differentiation, cystogenesis of the collecting ducts, and ureter development. [ABSTRACT FROM AUTHOR]

Failure of normal branching morphogenesis of the ureteric bud (UB), a key ontogenic process that controls organogenesis of the metanephric kidney, leads to congenital anomalies of the kidney and urinary tract (CAKUT), the leading cause of end-stage kidney disease in children. Recent studies have revealed a central role of the renin-angiotensin system (RAS), the cardinal regulator of blood pressure and fluid/electrolyte homeostasis, in the control of normal kidney development. Mice or humans with mutations in the RAS genes exhibit a spectrum of CAKUT which includes renal medullary hypoplasia, hydronephrosis, renal hypodysplasia, duplicated renal collecting system and renal tubular dysgenesis. Emerging evidence indicates that severe hypoplasia of the inner medulla and papilla observed in angiotensinogen ( Agt)- or angiotensin (Ang) II AT receptor ( AT R)-deficient mice is due to aberrant UB branching morphogenesis resulting from disrupted RAS signaling. Lack of the prorenin receptor ( PRR) in the UB in mice causes reduced UB branching, resulting in decreased nephron endowment, marked kidney hypoplasia, urinary concentrating and acidification defects. This review provides a mechanistic rational supporting the hypothesis that aberrant signaling of the intrarenal RAS during distinct stages of metanephric kidney development contributes to the pathogenesis of the broad phenotypic spectrum of CAKUT. As aberrant RAS signaling impairs normal renal development, these findings advocate caution for the use of RAS inhibitors in early infancy and further underscore a need to avoid their use during pregnancy and to identify the types of molecular processes that can be targeted for clinical intervention. [ABSTRACT FROM AUTHOR]

The kidney develops through mutual interactions between the metanephric mesenchyme and the ureteric bud, the former of which contains nephron progenitors that give rise to glomeruli and renal tubules. Bone morphogenetic protein (BMP) signaling and its modifiers play important roles in many steps of kidney development. BMP4 inhibits ureteric bud attraction, and the BMP antagonist Gremlin is essential for the initial stage of ureteric budding. During mid-gestation, BMP7 maintains the nephron progenitors and, at the same time, sensitizes them to the ureteric bud-derived differentiation signal. Crossveinless2 is a pro-BMP factor, and its absence leads to kidney hypoplasia. After birth, when nephron progenitors have disappeared, Dullard, a phosphatase that inactivates BMP receptors, keeps BMP signaling at an appropriate level. Deletion of Dullard results in excessive BMP signaling and apoptosis of the postnatal nephrons. In this review I discuss the similarities and differences of BMP functions in kidney development, as well as in diseases. [ABSTRACT FROM AUTHOR]

Congenital anomalies of the kidneys or lower urinary tract (CAKUT) encompass a spectrum of anomalies that result from aberrations in spatio-temporal regulation of genetic, epigenetic, environmental, and molecular signals at key stages of urinary tract development. The Rearranged in Transfection (RET) tyrosine kinase signaling system is a major pathway required for normal development of the kidneys, ureters, peripheral and enteric nervous systems. In the kidneys, RET is activated by interaction with the ligand glial cell line-derived neurotrophic factor (GDNF) and coreceptor GFRα1. This activated complex regulates a number of downstream signaling cascades (PLCγ, MAPK, and PI3K) that control proliferation, migration, renewal, and apoptosis. Disruption of these events is thought to underlie diseases arising from aberrant RET signaling. RET mutations are found in 5-30 % of CAKUT patients and a number of Ret mouse mutants show a spectrum of kidney and lower urinary tract defects reminiscent of CAKUT in humans. The remarkable similarities between mouse and human kidney development and in defects due to RET mutations has led to using RET signaling as a paradigm for determining the fundamental principles in patterning of the upper and lower urinary tract and for understanding CAKUT pathogenesis. In this review, we provide an overview of studies in vivo that delineate expression and the functional importance of RET signaling complex during different stages of development of the upper and lower urinary tracts. We discuss how RET signaling balances activating and inhibitory signals emanating from its docking tyrosines and its interaction with upstream and downstream regulators to precisely modulate different aspects of Wolffian duct patterning and branching morphogenesis. We outline the diversity of cellular mechanisms regulated by RET, disruption of which causes malformations ranging from renal agenesis to multicystic dysplastic kidneys in the upper tract and vesicoureteral reflux or ureteropelvic junction obstruction in the lower tract. [ABSTRACT FROM AUTHOR]

The mammalian kidney forms from several populations of progenitors that only persist during embryogenesis. The epithelial nephron progenitors reside in the cap mesenchyme (CM), whereas mesangial and endothelial cell progenitors reside in the neighboring stromal mesenchyme (SM). After a ureteric bud (UB) signal induces mesenchymal to epithelial transition of some CM cells, they form a nascent epithelial ball (a renal vesicle, or RV) that requires signals mediated by Notch receptors to separate proximal from distal fates. Two Notch receptors ( Notch1 and Notch2) and two ligands ( Jagged1 and Delta1) are expressed in the RV. Notably, instead of providing sufficient redundancy to ensure that losing any one allele will be inconsequential to human health, a reduction in the dose of one ligand ( Jagged1) or one receptor ( Notch2) is causally associated with a rare developmental syndrome (Alagille syndrome, or ALGS) affecting eye, kidney, liver, and craniofacial development. Here we discuss our current understanding of the molecular basis for the nonredundant role of Notch2 in this process, and the avenue for new therapeutic strategies that these insights provide. [ABSTRACT FROM AUTHOR]

Congenital anomalies of the kidney and urinary tract (CAKUT) cover a wide range of structural malformations that result from defects in the morphogenesis of the kidney and/or urinary tract. These anomalies account for about 40-50 % of children with chronic kidney disease worldwide. Knowledge from genetically modified mouse models suggests that single gene mutations in renal developmental genes may lead to CAKUT in humans. However, until recently, only a handful of CAKUT-causing genes were reported, most of them in familial syndromic cases. Recent findings suggest that CAKUT may arise from mutations in a multitude of different single gene causes. We focus here on single-gene causes of CAKUT and their developmental origin. Currently, more than 20 monogenic CAKUT-causing genes have been identified. High-throughput sequencing techniques make it likely that additional CAKUT-causing genes will be identified in the near future. [ABSTRACT FROM AUTHOR]

Vesicoureteric reflux (VUR) is a common congenital urinary tract defect that predisposes children to recurrent kidney infections. Kidney infections can result in renal scarring or reflux nephropathy defined by the presence of chronic tubulo-interstitial inflammation and fibrosis that is a frequent cause of end-stage renal failure. The discovery of mouse models with VUR and with reflux nephropathy has provided new opportunities to understand the pathogenesis of these conditions and may provide insight on the genes and the associated phenotypes that need to be examined in human studies. [ABSTRACT FROM AUTHOR]

The molecular basis of nephron progenitor cell renewal and differentiation into nascent epithelial nephrons is an area of intense investigation. Defects in these early stages of nephrogenesis lead to renal hypoplasia, and eventually hypertension and chronic kidney disease. Terminal nephron differentiation, the process by which renal epithelial precursor cells exit the cell cycle and acquire physiological functions is equally important. Failure of terminal epithelial cell differentiation results in renal dysplasia and cystogenesis. Thus, a better understanding of the transcriptional frameworks that regulate early and late renal cell differentiation is of great clinical significance. In this review, we will discuss evidence implicating the MDM2-p53 pathway in cell fate determination during development. The emerging central theme from loss- and gain-of-function studies is that tight regulation of p53 levels and transcriptional activity is absolutely required for nephrogenesis. We will also discuss how post-translational modifications of p53 (e.g., acetylation and phosphorylation) alter the spatiotemporal and functional properties of p53 and thus cell fate during kidney development. Mutations and polymorphisms in the MDM2-p53 pathway are present in more than 50 % of cancers in humans. This raises the question of whether sequence variants in the MDM2--p53 pathway increase the susceptibility to renal dysgenesis, hypertension or chronic kidney disease. With the advent of whole exome sequencing and other high throughput technologies, this hypothesis is testable in cohorts of children with renal dysgenesis. [ABSTRACT FROM AUTHOR]

Background: Little information is available on ureteral or vesical involvement in Henoch-Schönlein syndrome. To determine the features of this condition we performed a formal analysis of peer-reviewed scientific literature on this topic. Methods: The US National Library of Medicine database was used as the data source. All articles published as full-length articles or letters were collected. Reports published in languages other than English, French, German, Italian or Spanish were not considered. Results: We analyzed 32 reports describing 35 cases (24 male and 11 female subjects aged between 3.5 and 63, median 7.0 years) with ureteral ( n = 30), vesical ( n = 4), or both ureteral and vesical involvement ( n = 1). The presentation included colicky abdominal pain, macroscopic hematuria (sometimes containing blood clots), urinary tract infection or urinary retention. The diagnosis of ureteral involvement was often fortuitous. Patients with vesical involvement were managed conservatively. However, the majority of those with ureteral involvement were managed surgically. Conclusions: Ureteral or vesical involvement is unusual and likely underappreciated in Henoch-Schönlein syndrome. Improved recognition and wider appreciation of this involvement can help to avoid associated morbidity. Management must be individualized for each patient. A multidisciplinary approach may be of value in planning medical treatment, surgical intervention, and follow-up. [ABSTRACT FROM AUTHOR]

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder characterized by 2,8-dihydroxyadenine (2,8-DHA) crystalluria that can cause nephrolithiasis and chronic kidney disease. The aim of our study was to assess the clinical presentation, diagnosis, and outcome of APRT deficiency in a large pediatric cohort. All pediatric cases of APRT deficiency confirmed at the same French reference laboratories between 1978 and 2010 were retrospectively reviewed. Twenty-one patients from 18 families were identified. The median age at diagnosis was 3 years. Diagnosis was made after one or more episodes of nephrolithiasis (17 patients), after urinary tract infection (1 patient), and by family screening (3 patients). The diagnosis was based on stone analysis and microscopic examination of urine and/or enzymatic determination of APRT on red blood cells. All children had null APRT enzyme activity in erythrocytes. APRT gene sequencing was performed on 18 patients, revealing six homozygous and 12 compound heterozygous mutations. At diagnosis, half of the patients had decreased kidney function, and two children presented with acute renal failure. Allopurinol treatment was given to all patients at a median dose of 9 mg/kg/day. After a median follow-up of 5 years, all patients showed stabilization or improvement of kidney function, normal growth and development, and six patients had recurrence of nephrolithiasis. Based on these results, we conclude that an excellent outcome can be achieved in children with APRT deficiency who receive the proper treatment. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptors (Fgfrs) are expressed throughout the developing kidney. Several early studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB). Transgenic mice that over-express a dominant negative receptor isoform develop renal aplasia/severe dysplasia, confirming the importance of Fgfrs in renal development. Furthermore, global deletion of Fgf7, Fgf10, and Fgfr2IIIb (isoform that binds Fgf7 and Fgf10) in mice leads to small kidneys with fewer collecting ducts and nephrons. Deletion of Fgfrl1, a receptor lacking intracellular signaling domains, causes severe renal dysgenesis. Conditional targeting of Fgf8 from the MM interrupts nephron formation. Deletion of Fgfr2 from the UB results in severe ureteric branching and stromal mesenchymal defects, although loss of Frs2α (major signaling adapter for Fgfrs) in the UB causes only mild renal hypoplasia. Deletion of both Fgfr1 and Fgfr2 in the MM results in renal aplasia with defects in MM formation and initial UB elongation and branching. Loss of Fgfr2 in the MM leads to many renal and urinary tract anomalies as well as vesicoureteral reflux. Thus, Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development. [ABSTRACT FROM AUTHOR]

The kidney is formed by a reciprocally inductive interaction between two precursor tissues, the metanephric mesenchyme and the ureteric bud. This interaction can be divided into three processes: attraction of the ureteric bud toward the mesenchyme, maintenance of the mesenchyme in an undifferentiated state versus transition to an epithelial state, and further differentiation into multiple epithelial lineages, such as glomeruli and renal tubules. In this review we describe our recent findings related to each process. A mesenchymal nuclear zinc finger protein, Sall1, controls ureteric bud attraction by regulating a novel kinesin, Kif26b. The Sall1 gene is highly expressed in multipotent nephron progenitors in the mesenchyme, and these cells can partially reconstitute a three-dimensional structure in organ cultures following Wnt4 stimulation. While Notch2 is required for further differentiation of proximal nephron structures, ectopic Notch2 activation in the embryonic kidney depletes nephron progenitors, suggesting that Notch2 stabilizes-rather than dictates-nephron fate by shutting down the maintenance of undifferentiated progenitor cells. [ABSTRACT FROM AUTHOR]

Semaphorins are guidance proteins that play important roles in organogenesis and disease. Expression of class 3 semaphorins and their receptors is regulated during kidney development. Gain- and loss-of-function experiments demonstrated that tight semaphorin3a gene dosage is required for podocyte differentiation, and for the establishment of a normal glomerular filtration barrier. Sema3a modulates kidney vascular patterning acting as a negative regulator of endothelial cell migration and survival. Excess podocyte semaphorin3a expression causes glomerular disease in mice. In addition, Sema3a is a negative regulator of ureteric bud branching, whereas Sema3c is a positive regulator of ureteric bud and endothelial cell branching morphogenesis. In summary, secreted semaphorins modulate ureteric bud branching, vascular patterning, and podocyte-endothelial crosstalk, suggesting that they play a role in renal disease. Understanding the signaling pathways downstream from semaphorin receptors will provide insight into the mechanism of action of semaphorins in renal pathology. [ABSTRACT FROM AUTHOR]

Branching morphogenesis of the ureteric bud (UB) is a key developmental process that controls organogenesis of the entire metanephros. Notably, aberrant UB branching may result in a spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Genetic, biochemical and physiological studies have demonstrated that the renin-angiotensin system (RAS), a key regulator of the blood pressure and fluid/electrolyte homeostasis, also plays a critical role in kidney development. All the components of the RAS are expressed in the metanephros. Moreover, mutations in the genes encoding components of the RAS in mice or humans cause diverse types of CAKUT which include renal papillary hypoplasia, hydronephrosis, duplicated collecting system, renal tubular dysgenesis, renal vascular abnormalities, abnormal glomerulogenesis and urinary concentrating defect. Despite widely accepted role of the RAS in metanephric kidney and renal collecting system (ureter, pelvis, calyces and collecting ducts) development, the mechanisms by which an intact RAS exerts its morphogenetic actions are incompletely defined. Emerging evidence indicates that defects in UB branching morphogenesis may be causally linked to the pathogenesis of renal collecting system anomalies observed under conditions of aberrant RAS signaling. This review describes the role of the RAS in UB branching morphogenesis and highlights emerging insights into the cellular and molecular mechanisms whereby RAS regulates this critical morphogenetic process. [ABSTRACT FROM AUTHOR]

The article presents a case study related to patient suffering with acute kidney injury and perinephric fluid collection. Topics include the urethritis and ureteral obstruction secondary to Henoch-Schönlein purpura (HSP), complicated with subsequent urinoma, the patient has developed postrenal acute kidney injury (AKI) secondary to ureteral stenosis and a double-J stent has inserted, and the kidney functions and electrolyte imbalance has improved after insertion of the double-J stent.

A quiz concerning the IgA vasculitis and anuria is presented.

Spontaneous resolution of intrauterine pelvic dilatations after birth is an expected outcome. In nonobstructive pelvic dilatations, changes in ureteral and bladder physiology may also play a part. We aimed to demonstrate the effect of increased concentrations of bilirubin on ureteral and bladder muscles in vitro. Normal and pathologic concentrations of bilirubin (3.5×10-7–10-5M and 10-4–4×10-4M, respectively) caused no change in the basal ureter tension (343.9±29.4 mg). Normal concentrations of bilirubin caused no difference in basal bladder tension (430.2±70.2 mg), but pathologic concentrations caused a decrease of 303.8±52.9 mg. Normal and pathologic amounts of bilirubin were cumulatively applied to rabbit ureteral and bladder tissues both after reaching basal tension and when contracted with KCl (80 mM and 120 mM KCl for ureter and bladder, respectively). The cumulative addition of normal bilirubin concentrations to the ureteral tissues precontracted with KCl produced 86.4±7.2% relaxation, while the addition of pathologic bilirubin concentrations produced a relaxation of 133.9±17.4%, which was significantly higher ( p=0.04). Similarly, the addition of normal concentrations of bilirubin to the bladder tissues precontracted with KCl produced a maximal relaxation of 35.3±2.2%, while pathologic concentrations produced a maximal relaxation of 53.5±3.5%, which was significantly higher (0.001). Consequently, high concentrations of bilirubin caused a mild relaxation in basal ureteral and bladder tensions, while pathologically increased concentrations led to significant relaxation in both types of precontracted tissues. We suggest that high bilirubin levels may partly but not directly contribute to the spontaneous recovery of hydronephrosis because of the relaxation effect on bladder while probably causing susceptibility to urinary tract infections because of relaxation of both ureteral and bladder tissues. [ABSTRACT FROM AUTHOR]

In humans, the actions of angiotensin II are transduced through the AT1 and AT2 receptors which have recently been implicated in renal organogenesis. Polymorphisms in the human angiotensin II receptor genes have been linked to cardiovascular and nephrological disorders. In this study we evaluated 35 patients with either primary obstructive megaureter or posterior urethral valves. Each was genotyped for the A1166 AT1 polymorphism and the recently described A-1332G AT2 transition. The incidence of these genetic variants was also evaluated in normal controls without any ultrasonographic urological abnormalities. Similar to our previous findings in congenital urological abnormalities, the AT1 receptor genotype distribution did not differ between patients with either primary obstructive megaureter or posterior urethral valves versus controls. In contrast, compared with normal controls, there was a dramatic increase in the occurrence of the AT2 A-1332G transition in patients with primary obstructive megaureter (75.0% vs. 41.9% in controls, P<0.025). In patients with posterior urethral valves, there was no difference in the occurrence of the transition versus controls (36.9%, P=NS). Thus, there is no correlation between the AT1 receptor gene polymorphism and urological abnormalities. However there is an increased incidence in the AT2 genetic variant in patients with primary obstructive megaureter. [ABSTRACT FROM AUTHOR]

Abnormal development of the ureter during embryogenesis, when occurring in multiple family members, appears to be a genetically determined defect with autosomal dominant inheritance and high penetrance, which can lead to significant kidney damage, renal failure, and death. We have studied 48 individuals within a large kindred in which ureteral-related abnormalities (including vesicoureteral reflux, ureteropelvic junction obstruction, duplicated ureters, and medullary sponge kidney) were segregated. Family members who had not had previous diagnostic studies were evaluated for presence or absence of ureteral abnormalities and we attempted to map the locus for this familial ureteral abnormalities syndrome (FUAS). These studies identified 11 asymptomatic individuals, previously assumed to be unaffected, with minor abnormalities. When linkage analysis between the inheritance of ureteral abnormalities and six marker loci glyoxalase I (GLO-1), major histocompatibility antigens (HLA-A, B, and DR/DQ), D6S288, and factor XIII antigen (F13A1) on the short arm of chromosome 6 was performed, the lod scores significantly rejected linkage over a 77.1-cM distance. These findings are in contrast to previous data suggesting linkage between the presence of ureteral abnormalities and HLA, and indicate the possibility of genetic heterogeneity of FUAS. [ABSTRACT FROM AUTHOR]

Cyclic voiding cystourethrography (CVC) enhances the detection of vesicoureteric reflux (VUR). We investigated whether more-severe VUR may be overlooked, and whether older children are at risk of having their VUR missed with the conventional single-cycle study. Three hundred and seventy patients, 168 boys and 202 girls aged 1 month to 16 years, consecutively admitted over 1 year for suspicion of VUR, underwent two complete cycles of filling and voiding CVC. One hundred and four subjects, 33 boys and 71 girls, were older than 3 years (mean age 5.7 years, range 3.2–16 years). Sixty-six refluxing ureters from 51 patients were identified in the first cycle and 61 refluxing ureters from 45 patients were identified only with the second cycle. Four instances of grade IV VUR in 4 patients and three of grade V VUR in 3 patients were overlooked completely in the first cycle. Seven episodes of VUR ≤ grade III from 5 patients diagnosed in the first cycle were upgraded to ≥ grade IV at the second cycle. The presence of VUR was identified only in the second cycle in 35 of 74 subjects aged ≤ 3 years and in 10 of 22 aged >3 years (not significant). Of the 10 children aged >3 years, 2, who had diagnosis only at the second cycle, had ≥ grade IV VUR. More-severe VUR may be overlooked or down-graded in a single-cycle study. Two-cycle CVC is also useful in children older than 3 years. [ABSTRACT FROM AUTHOR]