European Association of Urology/European Society for Paediatric Urology Guidelines on Paediatric Urology: Summary of the 2024 Updates.

BACKGROUND AND OBJECTIVE: We present an overview of the 2024 updates for the European Association of Urology (EAU)/European Society for Paediatric Urology (ESPU) guidelines on paediatric urology to offer evidence-based standards for perioperative management, minimally invasive surgery (MIS), hydrocele, congenital lower urinary tract obstruction (CLUTO), trauma/emergencies, and fertility preservation. METHODS: A broad literature search was performed for each condition. Recommendations were developed and rated as strong or weak on the basis of the quality of the evidence, the benefit/harm ratio, and potential patient preferences. KEY FINDINGS AND LIMITATIONS: Recommendations for perioperative management include points related to fasting, premedication, antibiotic prophylaxis, pain control, and thromboprophylaxis in patients requiring general anaesthesia. MIS use is increasing in paediatric urology, with no major differences observed among different MIS approaches. For hydrocele, observation is the initial approach recommended. For persistent cases, treatment varies according to the type of hydrocele. CLUTO cases should be managed in tertiary centres with multidisciplinary expertise in prenatal and postnatal management. Neonatal valve ablation remains the mainstay of treatment, but associated bladder dysfunction requires continuous treatment. Among urological traumas and emergencies, renal trauma is still an important cause of morbidity and mortality. Conservative management has become the standard approach in haemodynamically stable children. Ischaemic priapism is a medical emergency and requires stepwise management. Initial management of nonischaemic priapism is conservative. Fertility preservation in prepubertal children and adolescents has become an increasingly relevant issue owing to the ever-increasing number of cancer survivors receiving gonadotoxic therapies. A major limitation is the scarcity of relevant literature. CONCLUSIONS AND CLINICAL IMPLICATIONS: This summary of the 2024 EAU/ESPU guidelines provides updated guidance for evidence-based management of some paediatric urological conditions. PATIENT SUMMARY: We provide a summary of the updated European Association of Urology/European Society for Paediatric Urology guidelines on paediatric urology. There are recommendations on steps to take before and immediately after surgery, management of hydrocele, congenital lower urinary tract obstruction, and urological trauma/emergencies, as well as preservation of fertility. Recommendations are based on a comprehensive review of recent studies.

Update and Summary of the European Association of Urology/European Society of Paediatric Urology Paediatric Guidelines on Vesicoureteral Reflux in Children.

BACKGROUND AND OBJECTIVE: The prescriptive literature on vesicoureteral reflux (VUR) is still limited and thus the level of evidence is generally low. The aim of these guidelines is to provide a practical approach to the treatment of VUR that is based on risk analysis and selective indications for both diagnostic tests and interventions. We provide a 2023 update on the chapter on VUR in children from the European Association of Urology (EAU) and European Society for Paediatric Urology (ESPU) guidelines. METHODS: A structured literature review was performed for all relevant publications published from the last update up to March 2022. KEY FINDINGS AND LIMITATIONS: The most important updates are as follows. Bladder and bowel dysfunction (BBD) is common in toilet-trained children presenting with urinary tract infection (UTI) with or without primary VUR and increases the risk of febrile UTI and focal uptake defects on a radionuclide scan. Continuous antibiotic prophylaxis (CAP) may not be required in every VUR patient. Although the literature does not provide any reliable information on CAP duration in VUR patients, a practical approach would be to consider CAP until there is no further BBD. Recommendations for children with febrile UTI and high-grade VUR include initial medical treatment, with surgical care reserved for CAP noncompliance, breakthrough febrile UTIs despite CAP, and symptomatic VUR that persists during long-term follow-up. Comparison of laparoscopic extravesical versus transvesicoscopic ureteral reimplantation demonstrated that both are good option in terms of resolution and complication rates. Extravesical surgery is the most common approach used for robotic reimplantation, with a wide range of variations and success rates. CONCLUSIONS AND CLINICAL IMPLICATIONS: This summary of the updated 2023 EAU/ESPU guidelines provides practical considerations for the management and diagnostic evaluation of VUR in children. ADVANCING PRACTICE: For children with VUR, it is important to treat BBD if present. A practical approach regarding the duration of CAP is to consider administration until BBD resolution. PATIENT SUMMARY: We provide a summary and update of guidelines on the diagnosis and management of urinary reflux (where urine flows back up through the urinary tract) in children. Treatment of bladder and bowel dysfunction is critical, as this is common in toilet-trained children presenting with urinary tract infection.

Endoscopic dilatation/incision of primary obstructive megaureter. A systematic review. On behalf of the EAU paediatric urology guidelines panel.

INTRODUCTION: Historically, ureteral reimplantation (UR) has been the gold standard for treatment of primary obstructive megaureter (POM) with declining renal function, worsening obstruction, or recurrent urinary tract infections. In infants, open surgery with reimplantation of a grossly dilated ureter into a small bladder, can be technically challenging with significant morbidity. Therefore, less invasive endoscopic management such as dilatation or incision of the ureter-vesical junction, has emerged as an alternative to reimplantation during the last decades. OBJECTIVE: To systematically evaluate the effectivity, safety, and potential benefits of endoscopic treatment (dilatation with or without balloon or incision) of POM in comparison to UR. STUDY DESIGN: A systematic review was conducted. Randomized controlled trials (RCTs), nonrandomized comparative studies (NRSs), and single-arm case series including a minimum of 20 participants and a mean follow-up more than 12 months were eligible for inclusion. RESULTS: Of 504 articles identified, 8 articles including 338 patients were eligible for inclusion (0 RCTs, 1 NRSs, and 7 case series). Age at time of surgery was minimum 15 days to a maximum of 192 months. Indications for endoscopic treatment (ET) included patients with loss of split renal function (>10%) and worsening of hydroureteronephrosis. The studies analysed reported a success rate ranging from 35% to 97%. Success was defined as stabilization of differential renal function without further procedures. A post-operative complication rate of 23-60% was reported (mostly transient haematuria, urinary tract infections and stent migration or intolerance). In 14% of the cases salvage UR following initial ET, was performed due to relapse of symptomatic POM. CONCLUSION: Endoscopic treatment for persistent or progressive POM in children is a minimally invasive alternative to UR with a long-term modest success rate. Additionally, it can be performed within a wide age span, with equal success rate and complication rates.

Maternal risk factors for posterior urethral valves.

Introduction: Posterior urethral valves (PUV) is a congenital disorder causing an obstruction of the lower urinary tract that affects approximately 1 in 4,000 male live births. PUV is considered a multifactorial disorder, meaning that both genetic and environmental factors are involved in its development. We investigated maternal risk factors for PUV. Methods: We included 407 PUV patients and 814 controls matched on year of birth from the AGORA data- and biobank and three participating hospitals. Information on potential risk factors (family history of congenital anomalies of the kidney and urinary tract (CAKUT), season of conception, gravidity, subfertility, and conception using assisted reproductive techniques (ART), plus maternal age, body mass index, diabetes, hypertension, smoking, and use of alcohol and folic acid) was derived from maternal questionnaires. After multiple imputation, adjusted odds ratios (aORs) were estimated using conditional logistic regression corrected for minimally sufficient sets of confounders determined using directed acyclic graphs. Results: A positive family history and low maternal age (<25 years) were associated with PUV development [aORs: 3.3 and 1.7 with 95% confidence intervals (95% CI) 1.4-7.7 and 1.0-2.8, respectively], whereas higher maternal age (>35 years) was associated with a lower risk (aOR: 0.7 95% CI: 0.4-1.0). Maternal preexisting hypertension seemed to increase PUV risk (aOR: 2.1 95% CI: 0.9-5.1), while gestational hypertension seemed to decrease this risk (aOR: 0.6 95% CI: 0.3-1.0). Concerning use of ART, the aORs for the different techniques were all above one, but with very wide 95% CIs including one. None of the other factors studied were associated with PUV development. Conclusion: Our study showed that family history of CAKUT, low maternal age, and potentially preexisting hypertension were associated with PUV development, whereas higher maternal age and gestational hypertension seemed to be associated with a lower risk. Maternal age and hypertension as well as the possible role of ART in the development of PUV require further research.

European Association of Urology and European Society for Paediatric Urology Guidelines on Paediatric Urinary Stone Disease.

CONTEXT: Paediatric stone disease is an important clinically entity and management is often challenging. Although it is known that the condition is endemic in some geographic regions of the world, the global incidence is also increasing. Patient age and sex; the number, size, location, and composition of the stone; and the anatomy of the urinary tract are factors that need to be taken into consideration when choosing a treatment modality. OBJECTIVE: To provide a general insight into the evaluation and management of urolithiasis in the paediatric population in the era of minimally invasive surgery. EVIDENCE ACQUISITION: A nonsystematic review of the literature on management of paediatric urolithiasis was conducted with the aim of presenting the most suitable treatment modality for different scenarios. EVIDENCE SYNTHESIS: Because of high recurrence rates, open surgical intervention is not the first option for paediatric stone disease, except for very young patients with very large stones in association with congenital abnormalities. Minimally invasive surgeries have become the first option with the availability of appropriately sized instruments and accumulating experience. Extracorporeal shockwave lithotripsy (SWL) is noninvasive and can be carried out as an outpatient procedure under sedation, and is the initial choice for management of smaller stones. However, for larger stones, SWL has lower stone-free rates and higher retreatment rates, so minimally invasive endourology procedures such as percutaneous nephrolithotomy and retrograde intrarenal surgery are preferred treatment options. CONCLUSIONS: Contemporary surgical treatment for paediatric urolithiasis typically uses minimally invasive modalities. Open surgery is very rarely indicated. PATIENT SUMMARY: Cases of urinary stones in children are increasing. Minimally invasive surgery can achieve high stone-free rates with low complication rates. After stone removal, metabolic evaluation is strongly recommended so that medical treatment for any underlying metabolic abnormality can be given. Regular follow-up with imaging such as ultrasound is required because of the high recurrence rates.

CDH12 as a Candidate Gene for Kidney Injury in Posterior Urethral Valve Cases: A Genome-wide Association Study Among Patients with Obstructive Uropathies.

BACKGROUND: Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development. OBJECTIVE: To identify genetic variants associated with kidney injury in patients with obstructive uropathy. DESIGN SETTING AND PARTICIPANTS: We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Signs of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. We used χ2 tests to calculate p values and odds ratios for >600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues. RESULTS AND LIMITATIONS: Despite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 gene was the most clear (p = 7.5 × 10-7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization. CONCLUSIONS: This study identified CDH12 as a candidate gene for kidney injury in PUV. PATIENT SUMMARY: We found that variants of the CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra (posterior urethral valves). This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition.

The prognostic value of testicular microlithiasis as an incidental finding for the risk of testicular malignancy in children and the adult population: A systematic review. On behalf of the EAU pediatric urology guidelines panel.

INTRODUCTION: The exact correlation of testicular microlithiasis (TM) with benign and malignant conditions remains unknown, especially in the paediatric population. The potential association of TM with testicular malignancy in adulthood has led to controversy regarding management and follow-up. OBJECTIVE: To determine the prognostic importance of TM in children in correlation to the risk of testicular malignancy or infertility and compare the differences between the paediatric and adult population. STUDY DESIGN: We performed a literature review of the Medline, Embase and Cochrane controlled trials databases until November 2020 according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) Statement. Twenty-six publications were included in the analysis. RESULTS: During the follow-up of 595 children with TM only one patient with TM developed a testicular malignancy during puberty. In the other 594 no testicular malignancy was found, even in the presence of risk factors. In the adult population, an increased risk for testicular malignancy in the presence of TM was found in patients with history of cryptorchidism (6% vs 0%), testicular malignancy (22% vs 2%) or sub/infertility (11-23% vs 1.7%) compared to TM-free. The difference between paediatric and adult population might be explained by the short duration of follow-up, varying between six months and three years. With an average age at inclusion of 10 years and testicular malignancies are expected to develop from puberty on, testicular malignancies might not yet have developed. CONCLUSION: TM is a common incidental finding that does not seem to be associated with testicular malignancy during childhood, but in the presence of risk factors is associated with testicular malignancy in the adult population. Routine monthly self-examination of the testes is recommended in children with contributing risk factors from puberty onwards. When TM is still present during transition to adulthood a more intensive follow-up could be considered.

EAU-ESPU pediatric urology guidelines on testicular tumors in prepubertal boys.

BACKGROUND: Testicular tumors in prepubertal boys account for 1-2% of all solid pediatric tumors. They have a lower incidence, a different histologic distribution and are more often benign compared to testicular tumors in the adolescent and adult group. This fundamental difference should also lead to a different approach and treatment. OBJECTIVE: To provide a guideline for diagnosis and treatment options in prepubertal boys with a testicular mass. METHOD: A structured literature search and review for testicular tumors in prepubertal boys was performed. All English abstracts up to the end of 2019 were screened, and relevant papers were obtained to create the guideline. RESULTS: A painless scrotal mass is the most common clinical presentation. For evaluation, high resolution ultrasound has a detection rate of almost 100%, alpha-fetoprotein is a tumor marker, however, is age dependent. Human chorionic gonadotropin (HCG) was not a tumor marker for testis tumors in prepubertal boys. CONCLUSION: Based on a summary of the literature on prepubertal testis tumors, the 2021 EAU guidelines on Pediatric Urology recommend a partial orchiectomy as the primary approach in tumors with a favorable preoperative ultrasound diagnosis.

Are there any benefits of using an inlay graft in the treatment of primary hypospadias in children? A systematic review and metanalysis.

INTRODUCTION: Dorsal inlay graft urethroplasty (DIGU) has been described as an effective method for hypospadias repair with the proposed advantage of reducing the risk of complications. We aimed to systematically assess whether DIGU has any additional advantages over standard tubularized incised plate urethroplasty (TIPU) repair in children with primary hypospadias. MATERIALS AND METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. The a priori protocol is available at the PROSPERO database (CRD42020168305). A literature search was conducted for relevant publications from 1946 until January 10, 2020 in seven different databases. Randomized controlled trials (RCTs), comparative studies (TIPU vs DIGU) and single arm case series (>20 cases) of DIGU were eligible for inclusion. Secondary hypospadias, two-stage repairs, disorders of sex development, significant curvature of >30°, and a mean or median follow-up of less than 12 months were excluded. DISCUSSION: A total of 499 articles were screened and 14 studies (3 RCTs, 5 non-randomized studies (NRSs), and 6 case series) with a total of 1753 children (distal: 1334 (76%) and proximal: 419 (24%)) were found eligible. Mean follow-up of the studies was between 16 and 77 months. DIGU was found superior to TIPU in decreasing meatal/neourethral stenosis (p = 0.02, 95% CI 0.02-0.78). All other parameters were found comparable including overall complications, fistula and glans dehiscence rates. Success rates were similar among the groups ranging between 48% and 96% for DIGU and 43-96% in the TIPU group. The lack of standardization in the definition of complications and success was the major limitation of this study. CONCLUSIONS: Using an inlay graft during primary hypospadias repair decreases the risk of meatal/neourethral stenosis. However, current evidence does not demonstrate superiority of DIGU over TIPU in terms of treatment success and overall complication rates.

Antenatal dexamethasone before asphyxia promotes cystic neural injury in preterm fetal sheep by inducing hyperglycemia.

Antenatal glucocorticoid therapy significantly improves the short-term systemic outcomes of prematurely born infants, but there is limited information available on their impact on neurodevelopmental outcomes in at-risk preterm babies exposed to perinatal asphyxia. Preterm fetal sheep (0.7 of gestation) were exposed to a maternal injection of 12 mg dexamethasone or saline followed 4 h later by asphyxia induced by 25 min of complete umbilical cord occlusion. In a subsequent study, fetuses received titrated glucose infusions followed 4 h later by asphyxia to examine the hypothesis that hyperglycemia mediated the effects of dexamethasone. Post-mortems were performed 7 days after asphyxia for cerebral histology. Maternal dexamethasone before asphyxia was associated with severe, cystic brain injury compared to diffuse injury after saline injection, with increased numbers of seizures, worse recovery of brain activity, and increased arterial glucose levels before, during, and after asphyxia. Glucose infusions before asphyxia replicated these adverse outcomes, with a strong correlation between greater increases in glucose before asphyxia and greater neural injury. These findings strongly suggest that dexamethasone exposure and hyperglycemia can transform diffuse injury into cystic brain injury after asphyxia in preterm fetal sheep.

Key neuroprotective role for endogenous adenosine A1 receptor activation during asphyxia in the fetal sheep.

BACKGROUND AND PURPOSE: The fetus is well known to be able to survive prolonged exposure to asphyxia with minimal injury compared with older animals. We and others have observed a rapid suppression of EEG intensity with the onset of asphyxia, suggesting active inhibition that may be a major neuroprotective adaptation to asphyxia. Adenosine is a key regulator of cerebral metabolism in the fetus. METHODS: We therefore tested the hypothesis that infusion of the specific adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), given before 10 minutes of profound asphyxia in near-term fetal sheep, would prevent neural inhibition and lead to increased brain damage. RESULTS: DPCPX treatment was associated with a transient rise and delayed fall in EEG activity in response to cord occlusion (n=8) in contrast with a rapid and sustained suppression of EEG activity in controls (n=8). DPCPX was also associated with an earlier and greater increase in cortical impedance, reflecting earlier onset of primary cytotoxic edema, and a significantly smaller reduction in calculated cortical heat production after the start of cord occlusion. After reperfusion, DPCPX-treated fetuses but not controls developed delayed onset of seizures, which continued for 24 hours, and sustained greater selective hippocampal, striatal, and parasagittal neuronal loss after 72-hour recovery. CONCLUSIONS: These data support the hypothesis that endogenous activation of the adenosine A1 receptor during severe asphyxia mediates the initial suppression of neural activity and is an important mechanism that protects the fetal brain.