Association between the imaging characteristics of renal abscess and vesicoureteral reflux.

INTRODUCTION: Renal abscesses are rare in pediatric populations. We aimed to highlight the differences in the computed tomography (CT) imaging characteristics of renal abscesses in patients with and without vesicoureteral reflux (VUR). MATERIALS AND METHODS: Thirteen children with renal abscesses were included and categorized into those with and without VUR. Blood and urine culture results were recorded as positive or negative. Imaging characteristics were recorded: with/without subcapsular fluid collection, with/without upper/lower pole involvement, and with single/multiple lesions in kidneys. Fisher's exact test was used for intergroup comparisons of the rate of positive pathogens and imaging characteristics. RESULTS: Nine patients had VUR (45.9%). Blood and urine culture were positive in two (15.4%) and seven cases (53.8%), respectively. There was no significant difference in the rate of pathogen-positive blood and urine cultures (blood culture positive/negative status with VUR vs. that without VUR = 2/7 vs. 0/4, p > 0.999, urine culture positive/negative status with VUR vs. that without VUR = 4/5 vs. 3/1, p = 0.559). The two groups differed significantly regarding subcapsular fluid collection presence (with/without subcapsular fluid collection with VUR vs. that without VUR = 9/0 vs 1/3, p = 0.014). There was no significant difference in upper/lower pole involvement (with/without involving upper/lower pole with VUR vs. that without VUR = 8/1 vs 2/2, p = 0.203). Patients with VUR were non-significantly more likely to have multiple lesions compared to those without VUR. CONCLUSIONS: VUR was associated with subcapsular fluid collection and possibly with multiple lesions, indicating the need for prompt detection of and specific treatment for VUR in cases with these findings.

Does the distal ureteral diameter ratio (UDR) matter in the surgical management of vesicoureteral reflux in children?

PURPOSE: To evaluate UDR reliability, sensitivity, specificity and to identify the best treatment basing on UDR among single or double endoscopic injections and ureteral reimplantation. METHODS: Data of patients affected by primary VUR and treated by endoscopic injection over a 10 years period were retrospectively analyzed. Two radiologist attributed reflux grade and UDR on voiding cystourethrogram twice and blinded. Follow-up focused on resolution after 1 or 2 endoscopic injections. Relation between UDR, reflux grade and outcomes were analyzed. RESULTS: Patient enrolled were 198. Low grade VUR was present in 24.8%, grade 3 in 41.6%, grade 4-5 in 33.6%. Resolution after one injection was obtained in 88 patients; among 110 not resolved 104 cases had a second injection. Success after 2 injections was reported in 138 cases. UDR showed a higher reliability compared with reflux grade both in intra than inter-reader measurement (ICC > 90%). Success after 1 or 2 injections was reported for UDR < 0.33 and UDR < 0.47 respectively. CONCLUSION: UDR shows to be a more reliable measurement that allows for an objective estimation of VUR severity and prognosis. It represents a quantitative parameter that might be useful to identify patients who may benefit endoscopic or surgical treatment, avoiding unnecessary under or over-treatment.

Utility of Positional Instillation of Contrast Cystography for Diagnosing Occult Vesicoureteral Reflux in Children: A Report of Two Cases.

Positional instillation of contrast (PIC) cystography is effective for detecting occult vesicoureteral reflux (VUR), which can not be revealed by standard voiding cystourethrography (VCUG). We experienced two cases of young female patients; one had repeated urinary tract infection with a negative VUR on standard VCUG, and the other had findings suggestive of reflux hydronephrosis and intolerance of standard VCUG. They underwent PIC cystography, and occult VUR was detected in both cases. Both were successfully treated with simultaneous endoscopic injection therapy with dextranomer/hyaluronic acid. PIC cystography is useful for detecting occult VUR in children with negative VUR findings on standard VCUG or who are unable to tolerate standard VCUG.

Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.

Hyaluronan, a double-edged sword in kidney diseases.

Over the years, hyaluronic acid (HA) has emerged as an important molecule in nephrological and urological studies involving extracellular matrix (ECM) organization, inflammation, tissue regeneration, and viral sensing. During this time, many have noted the perplexing double-edged nature of the molecule, at times promoting pro-fibrotic events and at other times promoting anti-fibrotic events. Different molecular weights of HA can be attributed to these disparities, though most studies have yet to focus on this subtlety. With regard to the kidney, HA is induced in the initial response phase of injury and is subsequently decreased during disease progression of AKI, CKD, and diabetic nephropathy. These and other kidney diseases force patients, particularly pediatric patients, to face dialysis, surgical procedures, and ultimately, transplant. To summarize the current literature for researchers and pediatric nephrologists, this review aims to expound HA and elucidate its paradoxical effects in multiple kidney diseases using studies that emphasize HA molecular weight when available.

Evaluation of screening with urine dipsticks and renal ultrasonography for 3-year-olds in Chiba City over 30 years.

BACKGROUND: Urinary screening for 3-year-olds cannot adequately detect congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: Urinary screening for 3-year-olds was investigated over 30 years. Dipsticks for proteinuria, hematuria, glycosuria, leukocyturia, and nitrite at first screening, and dipsticks, urinary sediments, and renal ultrasonography at second screening were performed. Screening results were evaluated. RESULTS: The positive rates of proteinuria, hematuria, leukocyturia, and nitrite relative to 218,831 children at the first screening were 1.0%, 4.6%, 2.3%, and 0.88%, respectively. Thirty-seven glomerular disease, 122 CAKUT, and 5 urological disease cases were found. We detected 6 stage 3-4 chronic kidney disease (CKD) and 3 end-stage kidney disease cases, including 3 CAKUT, comprising 2 bilateral renal hypoplasia and 1 vesicoureteral reflux (VUR), and 6 glomerular diseases, comprising 4 focal segmental glomerulosclerosis and 2 Alport syndrome. The positive rates relative to 218,831 children and CKD detection rates for each tentative diagnosis of mild hematuria, severe hematuria, proteinuria and hematuria, proteinuria, and suspected urinary tract infection were 1.4% and 0.67%, 0.11% and 3.7%, 0.01% and 28.6%, 0.02% and 45.0%, and 0.08% and 9.7%, respectively. Among 14 VUR cases with significant bacteriuria, 13 were found by leukocyturia, 12 had grade ≥ IV VUR, and 10 had severe renal scars. CONCLUSIONS: Nine stage 3-5 CKD cases comprising 3 CAKUT and 6 glomerular disease were found by urinary screening of 3-year-olds among 218,831 children. The combination of urine dipsticks including leukocyturia at the first screening and ultrasonography at the second screening appeared useful.

Mid-short-term risk factors for chronic renal failure in children with posterior urethral valve.

OBJECTIVES: To analyze the mid-short-term risk factors for chronic renal failure (CRF) in children with posterior urethral valve (PUV) after valve ablation. MATERIALS AND METHODS: A retrospective study of 143 patients with PUV who underwent operation was performed. Patients were divided into CRF group (n = 39) and non-CRF group (n = 104). Clinical data of both groups such as the first resection age, last resection age, number of operations, the maximal detrusor pressure (Pdetmax), and vesicoureteral reflux (VUR) were collected and analyzed. RESULTS: The first resection age, last resection age, and the Pdetmax of patients in the CRF group were higher than those of patients in the non-CRF group (P < 0.05). Multiple regression analysis showed that the indicators related to chronic renal failure were last resection age (ß = 1.034, P < 0.05) and Pdetmax (ß = 1.068, P < 0.05). The cut-off value of last resection age was 35.5 months, Pdetmax was 41.65 cmH2O. There was positive correlation of final blood creatinine with last resection age and Pdetmax. CONCLUSION: The last resection age and Pdetmax are the risk factors of chronic renal failure in children with PUV. A Pdetmax of lower than 41.65 cmH2O indicates a good prognosis of renal function in patients with PUV.

The 5:1 rule overestimates the needed tunnel length during ureteral reimplantation.

AIMS: Paquin asserts that in order for ureterovesical junctions (UVJs) to prevent reflux, the ureteral tunnel length-to-diameter ratio needs to be 5:1. We hypothesize that the surgical implementation of this observation results in an overestimation of the needed length-to-diameter ratio to prevent vesicoureteral reflux. METHODS: With finite elements, we model the urine storage phase of the bladder under nonlinear conditions. In the reference state, the bladder is assumed to be a sphere with an oblique straight elliptical hole as the UVJ. Broad parametric studies on different length-to-diameter ratios are performed as the bladder volume increases from 10% to 110% capacity. RESULTS: The capability of the UVJ to prevent reflux during storage depends on its length-to-diameter ratio. UVJs with larger length-to-diameter ratios lengthen and narrow as the bladder volume increases, causing the closure of the UVJ and rise in its flow resistance. Our model shows that the UVJ length-to-diameter ratio decreases as the bladder volume increases. The 5:1 ratio implemented at 80% capacity-approximate volume or bladder wall stretch during ureteroneocystostomy (UNC)-corresponds to 7:1 at the reference state-used by Paquin. The 5:1 ratio implemented at the reference state corresponds to 3:1 at 80% capacity. CONCLUSIONS: Our modeling results are consistent with Paquin's original observation on the significance of the UVJ length-to-diameter ratio in preventing reflux. They, however, indicate that the surgical implementation of this rule during UNC results in an overestimation of the requisite tunnel length-to-diameter ratio to prevent reflux. They also suggest that the UVJ closure is due to the bladder wall deformation rather than the pressure.

The utility of native ureter in the management of ureteral complications in children after renal transplantation.

BACKGROUND: Ureteral complications after renal transplantation in children are a major source of morbidity. Management is complex and variable. METHODS: With IRB approval, health records were retrospectively reviewed of patients who: were <18 years, underwent kidney transplant between 1997 and 2017, had at least 2 years of follow-up, and underwent interventions due to post-transplant ureteral complications. RESULTS: Of 136 patients, seventeen (13%) required ureteral intervention due to stricture (n = 3), reflux (n = 12), or both (n = 2). Transplant occurred at median 10.5 years (3.1-14.7). Reconstruction occurred at median 10 months (7-15) after transplant. Pre-existing bladder pathology was present in 6 (35%) patients. Four of five patients with strictures had at least one endoscopic balloon dilation. Ultimate management included reimplantation, ureteroureterostomy of native to transplant ureter, pyeloureterostomy to native ureter, multiple endoscopic interventions followed by a Boari flap, or multiple failed endoscopic interventions. Fourteen patients with VUR underwent reimplantation (n = 5), ureteroureterostomy of native to transplant ureter (n = 4), pyeloureterostomy to native ureter (n = 4), and one underwent endoscopic injection with Deflux of the transplant ureter. Only one patient had a non-functioning graft due to ureteral complication. All patients were alive at follow-up (median 17 years [12-19]). CONCLUSIONS: Transplant ureteral reflux and stricture are significant complications following pediatric renal transplantation and may require surgical management. In our population, reflux or stricture requiring ureteral reconstruction occurred in 10% and 4%, respectively. Endoscopic interventions were rarely successful. Native ureters were used for ureteral reconstruction in more than two thirds of patients should be considered in management of ureteral complications.

Risk factors for kidney scarring and vesicoureteral reflux in 421 children after their first acute pyelonephritis, and appraisal of international guidelines.

BACKGROUND: Acute pyelonephritis (AP) is a common bacterial infection in childhood. Follow-up guidelines on these children are controversial. This study aimed to identify risk factors for kidney scarring and vesicoureteral reflux (VUR). Furthermore, international follow-up guidelines were used for simulation to evaluate sensitivity and specificity. METHODS: Urinary culture-confirmed first-time AP patients (aged 0-14 years) were enrolled (n = 421) from review of patient charts. All underwent kidney ultrasound (US) and a technetium-99m-dimercaptosuccinic acid (DMSA) scan or technetium-99m-mercaptoacetyltriglycine scinti-renography (MAG3) at 4-6 months of follow-up. The international guidelines used for simulation were from the National Institute of Health UK (NICE), the American Association of Paediatrics (AAP) and the Swedish Paediatric Society (SPS). RESULTS: 17.8% presented with an abnormal DMSA/MAG3 at follow-up, 7.1% were diagnosed with VUR grades III-V and 4.7% were admitted for surgery. Non-Escherichia coli infections, abnormal kidney US, elevated creatinine and delayed response to treatment (>48 h) were risk factors for abnormal DMSA findings and VUR grades III-V. NICE and SPS guidelines showed best sensitivity in diagnosing VUR grades III-V (75%) compared with AAP (56%). CONCLUSIONS: Risk factors are helpful in identifying the children in need of further investigations and minimizing invasive work-up for the rest. International guidelines on follow-up detect a varying number of children with kidney damage and/or significant VUR. Future work must focus on identifying more specific risk factors, better imaging, or specific biomarkers, to enhance sensitivity and specificity in detecting the children at high risk for developing recurrent infections and/or nephropathy.

The pathogenesis and management of renal scarring in children with vesicoureteric reflux and pyelonephritis.

Bacterial urinary tract infections (UTIs) are one of the most common reasons for children to be admitted to hospital. Bacteria infect and invade the bladder (the lower urinary tract) and if the infection disseminates to the upper urinary tract, significant inflammation in the kidneys may arise. Inflammation is a double-edged sword: it is needed to clear bacteria, but if excessive, kidney tissue is injured. During injury, nephrons are destroyed and replaced with deposition of extracellular matrix and a renal scar. In this review, we explore the pathogenesis of UTIs and discuss the risk factors that result in dissemination of bladder infection to the kidneys. Three major risk factors predispose to kidney infections: the presence of vesicoureteric reflux, the presence of bladder and bowel dysfunction, and defects in the ability of the host immune response to clear bacteria. In this review, we will discuss these factors, their relationship to renal scarring, and potential treatments that might be beneficial to prevent renal scar formation in children.

Antibiotic prophylaxis for prevention of urinary tract infections in the first year of life in children with vesicoureteral reflux diagnosed in the workup of antenatal hydronephrosis: a systematic review.

BACKGROUND: Children with antenatal hydronephrosis (ANH) diagnosed with postnatal asymptomatic vesicoureteral reflux (VUR) are thought to be at higher risk of urinary tract infection (UTI). As such, continuous antibiotic prophylaxis (CAP) is empirically recommended until age of toilet training; however, there are limited data to support this. The objective of this systematic review was to summarize the existing data and compare UTI rates in infants with asymptomatic VUR on CAP during the first year of life, to those not on CAP. Secondary objectives were to determine associated risk factors with UTI development. METHODS: A systematic search of all relevant studies and abstracts was conducted using 4 electronic databases by utilizing appropriate key words by an expert hospital librarian. Eligible studies included children with prenatal hydronephrosis, asymptomatic VUR with or without CAP, and reported on development of UTI in the first year. RESULTS: Of 6903 citations screened, 18 were selected, giving a total population of 829 (69.4% male, median age 57 days) who met the inclusion criteria. Most studies were retrospective and of low-quality evidence. Overall, 15.4% of patients developed at least one breakthrough UTI and females had a higher risk of UTI (odds ratio (OR) 2.3, 95% CI 1.1-4.7). Comparison with children not taking CAP was not readily reported, and meta-analysis could not be completed. CONCLUSIONS: Randomized controlled trials and standardized reporting of clinical variables are required to understand the protective effect of antibiotic prophylaxis in this cohort.

Necessity of performing voiding cystourethrography for children with unilateral multicystic dysplastic kidney.

BACKGROUND: The purpose of this study was to resolve the clinical question as to whether all patients with unilateral multicystic dysplastic kidney (MCDK) should receive voiding cystourethrography (VCUG). METHODS: This is a retrospective study using cross-sectional analysis. Seventy-five children with unilateral MCDK were enrolled, excluding patients with other genetic or chromosome abnormalities, spinal cord diseases, or anal atresia. We reviewed their records from medical charts and calculated risk factors for abnormal VCUG using multivariate logistic regression analysis. RESULTS: Abnormal VCUG findings were present in 24 of 75 patients (32.0%), specifically, vesicoureteral reflux (VUR) in 8 (10.6%), including high-grade VUR in 2 (2.7%), and only lower urinary tract or bladder disease in 16 (21.3%). In multivariate analysis, only abnormal findings by ultrasonography was an independent risk factor for abnormal VCUG findings with statistical significance in multivariate analysis (OR 6.57; 95% CI 1.99-26.26; P = 0.002). When we excluded five patients who showed similar findings by ultrasonography and VCUG, abnormal findings by ultrasonography were again calculated as an independent risk factor (OR 4.44; 95% CI 1.26-28.42; P = 0.02). Sensitivity, specificity, positive predictive value, and negative predictive value of abnormal findings by ultrasonography to predict urologic anomalies by VCUG in these children were 83%, 59%, 49%, and 88%, respectively. Two children required a third ultrasonography to detect abnormal findings. CONCLUSIONS: We can select, using only abnormal findings by ultrasonography, children with unilateral MCDK who should undergo VCUG. We would also like to emphasize that ultrasonography should be performed repeatedly to detect congenital anomalies of the urinary tract.

Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. RESULTS: In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

Heterozygous loss-of-function mutation in Odd-skipped related 1 (Osr1) is associated with vesicoureteric reflux, duplex systems, and hydronephrosis.

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.

Laparoscopic vesico-ureteral reimplantation with Lich-Gregoir approach in children: medium term results of 159 renal units in 117 children.

PURPOSE: Vesico-ureteral reflux (VUR) represents one of the most significant risk factors for acute pyelonephritis in children. Surgery is an important part of its management. Laparoscopic ureteric reimplantation using the Lich-Gregoir technique is an option for VUR. The aim of this study is to assess short- and medium-term outcomes of this approach. MATERIALS AND METHODS: This is a retrospective study including all children with VUR treated by laparoscopic extravesical ureteral reimplantation with the Lich-Gregoir technique in University Hospital of Saint-Etienne from August 2007 to May 2016. Surgery was performed after the age of 12 months in cases with repeated urinary tract infection (UTI) and a deterioration of renal function. All patients were followed-up post operatively. RESULTS: 117 children (92 girls, 25 boys) representing 159 renal units were included. The mean age at surgery was 47.1 months (±32.7 months). The mean follow-up was 59.3 months (±31 months). The resolution rate for VUR in terms of no febrile urinary UTIs was 98.3%. The mean operative time was 96 min (±37.7 min) for unilateral procedures and 128 min (±46.1 min) for bilateral procedures. The mean hospital stay was 25.3 h (±6.3 h). There was no difference between males and females regarding age, weight, renal function or follow-up duration. CONCLUSIONS: Laparoscopic reimplantation with Lich-Gregoir technique is an efficient, quick and safe technique for the management of VUR. The success rate is comparable to open techniques with the advantages of laparoscopic approach; this can potentially be performed as a Day Case procedure.

[Transurethral Injection Using Deflux for Vesicoureteral Reflux in Three Adult Women with Frequent Febrile Urinary Tract Infections].

We report three patients with frequent febrile urinary tract infections (fUTI) who underwent transurethral injection therapy with Deflux for vesicoureteral reflux (VUR). The first case was in a 52-yearold woman who was initially diagnosed with right grade II and left grade I VUR at 18 years of age. She frequently experienced fUTI due to VUR. The second case was in a 29-year-old woman. At age 23,she was diagnosed with right grade III VUR when she developed fUTI. After that,she repeatedly developed fUTI. The third case was in a 40-year-old woman who had frequently experienced fUTI since 25 years of age and had gradually become antibiotics-resistant. She was diagnosed with right grade III VUR when she was referred to our hospital. No visible reflux was confirmed by postoperative voiding cystourethrography after the patients underwent transurethral injection using Deflux. One patient developed fUTI once after surgery,but there were no perioperative complications and no recurrences. Transurethral injection using Deflux for VUR might therefore be safe and effective for treating VUR in adult female patients.

New congenital anomalies of the kidney and urinary tract and outcomes in Robo2 mutant mice with the inserted piggyBac transposon.

BACKGROUND: Disruption of ROBO2 in humans causes vesicoureteral reflux (VUR)/congenital anomalies of the kidney and urinary tract (CAKUT). PiggyBac (PB) is a DNA transposon, and its insertion often reduces-but does not eliminate-gene expression. The Robo2 insertion mutant exhibited non-dilating VUR, ureteropelvic junction obstruction (UPJO) not found in reported models. We studied the incidence and outcomes of VUR/CAKUT in this mutant and explored the relationship between Robo2 gene expression and the occurrence and severity of VUR/CAKUT. METHODS: The urinary systems of newborn mutants were evaluated via Vevo 770 micro-ultrasound. Some of the normal animals-and all of the abnormal animals-were followed to adulthood and tested for VUR. Urinary obstruction experiments were performed on mice with hydronephrosis. The histology of the kidney and ureter was examined by light microscopy and transmission electron microscopy. Robo2 (PB/PB) mice were crossed with Hoxb7/myr-Venus mice to visualize the location of the ureters relative to the bladder. RESULTS: In Robo2 (PB/PB) mice, PB insertion led to an approximately 50 % decrease in Robo2 gene expression. The most common (27.07 %, 62/229) abnormality was non-dilating VUR, and no statistically significant differences were found between age groups. Approximately 6.97 % displayed ultrasound-detectable CAKUT, and these mice survived to adulthood without improvement. No severe CAKUT were found in Robo2 (PB/+) mice. The refluxing ureters showed disorganized smooth muscle fibers, reduced muscle cell populations, intercellular edema and intracytoplasmic vacuoles in smooth muscle cells. Both UPJ and UVJ muscle defects were noted in Robo2 (PB/PB) mice. CONCLUSIONS: Robo2 (PB/PB) mice is the first Robo2-deficient mouse model to survive to adulthood while displaying non-dilating VUR, UPJO, and multiple ureters with blind endings. The genetic background of these mutants may influence the penetrance and severity of the CAKUT phenotypes. VUR and other CAKUT found in this mutant had little chance of spontaneous resolution, and this requires careful follow-up. We reported for the first time that the non-dilated refluxing ureters showed disorganized smooth muscle fibers and altered smooth muscle cell structure, more accurately mimicking the characteristics of human cases. Future studies are required to test the role of Robo2 in the ureteric smooth muscle.

Renal scarring and chronic kidney disease in children with spina bifida in a multidisciplinary Malaysian centre.

AIMS: The aim of this study was to determine the occurrence of renal cortical scarring and chronic kidney disease (CKD) in children with neurogenic bladder secondary to spina bifida (SB) managed at the Universiti Kebangsaan Malaysia Medical Centre. The secondary objective was to identify the clinical factors associated with these adverse outcomes. METHODS: The medical records of 56 children managed from 1997 were available. Socio-demographic and clinical data for SB children managed for a minimum of 2 years (n = 45) were reviewed. This included age at referral, gender, ethnicity, duration of care, type of SB lesion, presence of vesico-ureteric reflux (VUR), symptomatic urinary tract infections, bladder trabeculation, catheterisations and renal function. RESULTS: Forty-nine per cent of SB lesions were open myelomeningocoele, 40% were closed lesions and 11% were occult. Majority (96%) were at lumbar L3 or below. Twenty-nine children (64.5%) were referred before 6 months of age (mean15.8 months; range newborn to 125 months). Thirty-five (77.8%) had neurogenic bladder and 31(69%) had neurogenic bowel. Sixteen developed renal scarring and six, CKD. Late referral (≥6 months of age), small kidneys at referral, dilating VUR and bladder trabeculation were significant independent factors associated with scarring. On multivariate analysis, late referral (odds ratio (OR) 17.4; 95% confidence interval (CI) 1.26-238.7) and dilating VUR (OR 137.0; CI 6.4-2921.1) remained significant. CONCLUSION: Prevention of renal scarring and CKD remains a challenge in Malaysia even with multidisciplinary proactive care of SB children. Early referrals and more stringent management strategies for dilating VUR are still required.

Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, >90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.