CT, US and MRI of xanthine urinary stones: in-vitro and in-vivo analyses.

BACKGROUND: Xanthine urinary stones are a rare entity that may occur in patients with Lesch-Nyhan syndrome receiving allopurinol. There is little literature describing imaging characteristics of these stones, and the most appropriate approach to imaging these stones is therefore unclear. We performed in-vitro and in-vivo analyses of xanthine stones using computed tomography (CT) at different energy levels, ultrasound (US), and magnetic resonance imaging (MRI). METHODS: Five pure xanthine stones from a child with Lesch-Nyhan were imaged in-vitro and in-vivo. CT of the stones was performed at 80 kVp, 100 kVp, 120 kVp and 140 kVp and CT numbers of the stones were recorded in Hounsfield units (HU). US of the stones was performed and echogenicity, acoustic shadowing and twinkle artifact were assessed. MRI of the stones was performed and included T2-weighted, ultrashort echo-time-weighted and T2/T1-weighted 3D bFFE sequences and signal was assessed. RESULTS: In-vitro analysis on CT demonstrated that xanthine stones were radiodense and the average attenuation coefficient did not differ with varying kVp, measuring 331.0 ± 51.7 HU at 80 kVp, 321.4 ± 63.4 HU at 100 kVp, 329.7 ± 54.2 HU at 120 kVp and 328.4 ± 61.1 HU at 140 kVp. In-vivo analysis on CT resulted in an average attenuation of 354 ± 35 HU. On US, xanthine stones where echogenic with acoustic shadowing and twinkle artifact. On MRI, stones lacked signal on all tested sequences. CONCLUSION: Xanthine stone analyses, both in-vitro and in-vivo, demonstrate imaging characteristics typical of most urinary stones: dense on CT, echogenic on US, and lacking signal on MRI. Therefore, the approach to imaging xanthine stones should be comparable to that of other urinary stones.

Exploring the Association of Asthma with Urinary Stone Disease: Results from the National Health and Nutrition Examination Survey 2007-2014.

BACKGROUND: The prevalence of urinary stone disease (USD) and asthma is rising and has recently been associated in a pediatric population. OBJECTIVE: To investigate the association between asthma and USD in a nationally representative adult population. DESIGN, SETTING, AND PARTICIPANTS: We analyzed the National Health and Nutrition Examination Survey 2007-2014, a US population-based cross-sectional study. A history of asthma and USD was obtained by self-report to questionnaires. USD severity was represented by graded stratification into non-stone formers, single stone formers, and recurrent stone formers (>2 stones). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) for asthma were calculated for respondents with USD and separately for the graded USD groups. Survey-weighted logistic regression models included adjustments for demographics (model A), medical information (model B), and for relevant medications (model C). RESULTS AND LIMITATIONS: A total of 20 906 participants aged ≥20 yr were included in the analysis. Of these, 9.2% reported of having a history of kidney stones. Logistic regression analysis adjusted for demographics, medical conditions, and medications showed that stone formers had significantly increased odds of asthma (odds ratio=1.23; 95% confidence interval: 1.03-1.47; p=0.023). Separate logistic regression analysis demonstrated a graded association between single and recurrent stone formers and the odds of having asthma (p=0.01), which remained significant in the 20-50-yr-old population and the diabetic population, especially for recurrent stone formers. Causal relationships were limited by cross-sectional nature of the study. CONCLUSIONS: Increasing severity of USD is associated with an increase in odds for asthma among American adults, providing impetus for future studies into the mechanisms explaining this phenomenon. PATIENT SUMMARY: In this report, we looked at self-reported histories of asthma and urinary stone disease (USD) using information from a large US population. We found that asthma was associated with USD; however, further studies are needed to elucidate this relationship.

Does total testicular volume predict testicular volume difference in adolescent males with varicocele?

ABSTRACT Introduction: We evaluated the relationship between total testicular volume (TTV) and testicular volume differential (TVD) in adolescent males with varicocele. Both low TTV and high TVD have been independently associated with higher incidences of infertility later in life, but a predictive relationship between TTV and TVD directly has yet to be described. Materials and Methods: We retrospectively analyzed a database of Tanner 5 boys ages 16-21 who presented with varicocele at a single institution between 2009 and 2017. All patients had a scrotal sonogram prior to surgical intervention. TTV and TVD were calculated for each individual and four non-exclusive groupings of patients were created for statistical analysis. We chose 30 cc as a cut off value for low TTV based on prior studies. Results: 209 patients met our inclusion criteria. Mean age was 18.3 years (16-21, SD 1.7) with a mean total testicular volume of 36 cc (13.5-78.2, SD 11.1). Cut off points of TVD of 20% and TTV of 30 cc were used to separate patients. There were 65 boys (31%) with TTV < 30 cc and 58 boys (28%) with TVD ≥ 20%. Among males with TTV < 30 cc, 23 (35%) had a TVD ≥ 20%. Among males with TTV ≥ 30 cc, 35 (24%) had a TVD ≥ 20%. The relationship between TVD and TTV was found to be non-significant (p > 0.05). Discussion: Adolescent varicoceles continue to pose a challenge to pediatric urologists. The dilemma of over-aggressive treatment has proven difficult to balance with the risk of infertility. We hoped that elucidating the relationship between TTV and TVD could be useful in identifying patients who are at greater risk for infertility while decreasing the need for more intrusive testing, such as semen analysis, in an adolescent population. We looked at the direct relationship between low TTV and high TVD. In our population, there was a non-significant relationship between TTV < 30 cc and TVD ≥ 20% (p > 0.05) indicating that in adolescents with varicocele, TTV and TVD are independent variables. Our study limitations include the inherent user dependent bias of ultrasound measurements and data collection at a single institution with high ethnic diversity, possibly not comparable to all patient populations. Conclusions: Low TTV (< 30 cc) itself is not predictive of high TVD (≥ 20%) in adolescent boys with varicocele, despite their reported independent associations with impaired fertility in other studies.

Does total testicular volume predict testicular volume difference in adolescent males with varicocele?

INTRODUCTION: We evaluated the relationship between total testicular volume (TTV) and testicular volume differential (TVD) in adolescent males with varicocele. Both low TTV and high TVD have been independently associated with higher incidences of infertility later in life, but a predictive relationship between TTV and TVD directly has yet to be described. MATERIALS AND METHODS: We retrospectively analyzed a database of Tanner 5 boys ages 16-21 who presented with varicocele at a single institution between 2009 and 2017. All patients had a scrotal sonogram prior to surgical intervention. TTV and TVD were calculated for each individual and four non-exclusive groupings of patients were created for statistical analysis. We chose 30 cc as a cut off value for low TTV based on prior studies. RESULTS: 209 patients met our inclusion criteria. Mean age was 18.3 years (16-21, SD 1.7) with a mean total testicular volume of 36 cc (13.5-78.2, SD 11.1). Cut off points of TVD of 20% and TTV of 30 cc were used to separate patients. There were 65 boys (31%) with TTV < 30 cc and 58 boys (28%) with TVD ≥ 20%. Among males with TTV < 30 cc, 23 (35%) had a TVD ≥ 20%. Among males with TTV ≥ 30 cc, 35 (24%) had a TVD ≥ 20%. The relationship between TVD and TTV was found to be non-significant (p > 0.05). DISCUSSION: Adolescent varicoceles continue to pose a challenge to pediatric urologists. The dilemma of over-aggressive treatment has proven difficult to balance with the risk of infertility. We hoped that elucidating the relationship between TTV and TVD could be useful in identifying patients who are at greater risk for infertility while decreasing the need for more intrusive testing, such as semen analysis, in an adolescent population. We looked at the direct relationship between low TTV and high TVD. In our population, there was a non-significant relationship between TTV < 30 cc and TVD ≥ 20% (p > 0.05) indicating that in adolescents with varicocele, TTV and TVD are independent variables. Our study limitations include the inherent user dependent bias of ultrasound measurements and data collection at a single institution with high ethnic diversity, possibly not comparable to all patient populations. CONCLUSIONS: Low TTV (< 30 cc) itself is not predictive of high TVD (≥ 20%) in adolescent boys with varicocele, despite their reported independent associations with impaired fertility in other studies.

Diagnosis and management of non-calcium-containing stones in the pediatric population.

Compared to adults, urolithiasis is less common in children, with a definite rise in incidence, especially among young adults (Tasian et al. in Clin J Am Soc Nephrol 11:488, 2016). In the last 25 years, the incidence in children has increased by approximately 6-10% annually, for reasons still unknown, with an associated significant increase in related health care-related expenditures (Hyams and Matlaga in Transl Androl Urol 3(3):278-83, 2014). It has been shown that there is twice as high a risk of chronic kidney disease (CKD) or end stage renal disease (ESRD) in stone formers compared to non-stone formers (Tasian et al. 2016). While calcium-containing stones are by far the most common category of stone encountered in both children and adults, non-calcium stones are more common in children than adults and have been shown in several studies to be associated with greater morbidity and lower renal function than calcium stones (Issler et al. in BMC Nephrol 18(1):136, 2017; Gambaro et al. in J Urol 198:268-273, 2017). This could be related to the challenges in the management of non-calcium-containing stones due to associated infection or metabolic derangements, further leading to recurrence and loss of renal function. There is currently a gap in our understanding of how to appropriately and effectively encounter and manage patients with non-calcium-containing stones, as such cases are encountered less frequently. Identification of stone composition and appropriate management is very important to reduce serious complications and recurrence, especially in non-calcium stones. We present a review of diagnosis and management of non-calcium-containing stones in the pediatric population, in hopes of providing more clarity to providers and promoting a consideration of non-calcium stone composition with all children presenting with urolithiasis.

International Children's Continence Society standardization report on urodynamic studies of the lower urinary tract in children.

AIMS: The objective of this document created by the ICCS standardization subcommittee is to provide a uniform guideline on measurement, quality control and documentation of urodynamic studies in children. METHODS: This guideline was created using expert opinion and critical review of the published literature on urodynamic studies in children. Currently no standardized guideline or level 1 data exists on the proper technique for this subject matter. RESULTS: The document provides a throughout explanation on how to approach a child who presents with lower urinary tract dysfunction, whether it be of neurogenic, anatomic or functional origin. Formation of an urodynamic question after a comprehensive history and physical examination is paramount in selecting the urodynamic study(ies) that will be most appropriate for each child. Appropriate application of each test with careful consideration of the needs of the child and family will provide the most accurate and reproducible results. Recommendations on how to execute each of the components of an urodynamic study as well as interpretation are included in the document. CONCLUSIONS: Urodynamic studies have become a major tool in evaluating lower urinary tract dysfunction in children. There are many subtleties in performing these studies in children in juxtaposition to adults; therefore, adaptations specific to children must be made to achieve accurate and reproducible results. Uniformity in how the studies are conducted from center to center will allow for healthier transparency and enhanced comparison of results in both clinical and research situations.

Murine bladder wall biomechanics following partial bladder obstruction.

Evaluation of bladder wall mechanical behavior is important in understanding the functional changes that occur in response to pathologic processes such as partial bladder outlet obstruction (pBOO). In the murine model, the traditional approach of cystometry to describe bladder compliance can prove difficult secondary to small bladder capacity and surgical exposure of the bladder. Here, we explore an alternative technique to characterize murine mechanical properties by applying biaxial mechanical stretch to murine bladders that had undergone pBOO. 5-6 week old female C57/Bl6 mice were ovariectomized and subjected to pBOO via an open surgical urethral ligation and sacrificed after 4 weeks (n=12). Age matched controls (n=6) were also analyzed. Bladders were separated based on phenotype of fibrotic (n=6) or distended (n=6) at the time of harvest. Biaxial testing was performed in modified Kreb's solution at 37°C. Tissue was preconditioned to 10 cycles and mechanical response was evaluated by comparing axial strain at 50kPa. The normal murine bladders exhibited anisotropy and were stiffer in the longitudinal direction. All mice showed a loss of anisotropy after 4 weeks of pBOO. The two phenotypes observed after pBOO, fibrotic and distended, exhibited less and more extensibility, respectively. These proof-of-principle data demonstrate that pBOO creates quantifiable changes in the mechanics of the murine bladder that can be effectively quantified with biaxial testing.

Observation of patients with vesicoureteral reflux off antibiotic prophylaxis: physician bias on patient selection and risk factors for recurrent febrile urinary tract infection.

PURPOSE: Observation off continuous antibiotic prophylaxis is an option for vesicoureteral reflux. We evaluated the characteristics of patients observed off continuous antibiotic prophylaxis and risk factors for febrile urinary tract infection. MATERIALS AND METHODS: We identified children 1 to 18 years old with primary vesicoureteral reflux between January 1, 2010 and December 31, 2010. We excluded patients with prior surgical correction from analysis. We recorded age, gender, race/ethnicity, primary language, insurance carrier, age at vesicoureteral reflux diagnosis, initial presentation and vesicoureteral reflux severity. We quantified bladder and bowel dysfunction with a validated questionnaire if toilet trained. We compared patients off vs on continuous antibiotic prophylaxis with the chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. We used a univariate Cox proportional hazards model to assess predictors of febrile urinary tract infection during observation off continuous antibiotic prophylaxis. RESULTS: Of 529 eligible patients 224 were observed off continuous antibiotic prophylaxis. Patients off continuous antibiotic prophylaxis tended to be older (p <0.001), to be older at diagnosis (p <0.001), to have an initial presentation other than febrile urinary tract infection (p = 0.05), to have nondilating vesicoureteral reflux on most recent cystogram (p <0.001) and to have lower bladder/bowel dysfunction scores if toilet trained (p <0.001). Of the patients off continuous antibiotic prophylaxis a febrile urinary tract infection developed in 19 (8.5%). Risk factors associated with febrile urinary tract infection included initial presentation of multiple febrile urinary tract infections (p = 0.03), older age at diagnosis (p = 0.03) and older age starting observation off continuous antibiotic prophylaxis (p = 0.0003). CONCLUSIONS: Criteria to select patients with vesicoureteral reflux for observation off continuous antibiotic prophylaxis remain poorly defined in the literature. Observation will fail in a subset of patients with vesicoureteral reflux. Physician biases regarding patient selection for observation off continuous antibiotic prophylaxis should be considered when interpreting studies that evaluate treatment strategies.

Use of validated bladder/bowel dysfunction questionnaire in the clinical pediatric urology setting.

PURPOSE: Questionnaires to quantify pediatric bladder/bowel dysfunction have recently been developed as research instruments. We evaluated our use of a bladder/bowel dysfunction questionnaire in a busy clinical setting. MATERIALS AND METHODS: We distributed a validated bladder/bowel dysfunction questionnaire to all new pediatric urology outpatients older than age 4 years from May 1 to July 31, 2010. We instructed families to complete the questionnaire without assistance. Physicians were blinded to responses during the study period. We compared total scores between groups of patients with bladder/bowel dysfunction related and bladder/bowel dysfunction unrelated primary diagnoses. We also compared individual item scores pertaining to urinary incontinence, dysuria, nocturnal enuresis and constipation in patients with those specific primary ICD-9 diagnosis codes to those of other bladder/bowel dysfunction related diagnoses. RESULTS: Of 358 questionnaires reviewed 91 (25%) could not be adequately scored. Of the remaining 267 patients 134 had bladder/bowel dysfunction related diagnoses and 133 had bladder/bowel dysfunction unrelated diagnoses. The patients with bladder/bowel dysfunction related diagnoses had a higher score on the validated questionnaire (p <0.001). Patients with primary ICD-9 diagnoses for urinary incontinence (p = 0.0026, p = 0.0164), dysuria (p = 0.008) and nocturnal enuresis (p <0.0001) had higher scores on corresponding items of the questionnaire than those with other bladder/bowel dysfunction related diagnoses. The ICD-9 diagnosis of constipation was not associated with higher scores for constipation related items. CONCLUSIONS: A validated bladder/bowel dysfunction questionnaire is a useful tool in the pediatric urology clinical setting that correlates well with physician assessment. The questionnaire can help patients and their families better define their bladder/bowel symptoms before their visit. Some families will not be able to fill out the questionnaire appropriately.

Modulation of the hypoxic response following partial bladder outlet obstruction.

PURPOSE: Tissue level hypoxia has been noted in animal models of partial bladder outlet obstruction. The key mechanisms linking hypoxia and obstruction induced bladder dysfunction remain unknown. 2-Methoxyestradiol is a natural derivative of 17ß-estradiol and is currently used as an oncologic agent for its ability to regulate the hypoxia pathway. We investigated the ability of 2-methoxyestradiol to modulate the hypoxia response in a mouse model of bladder obstruction. MATERIALS AND METHODS: A group of 5 to 6-week-old female C57BL/6 mice underwent oophorectomy and partial bladder outlet obstruction. Obstructed animals received a subcutaneous pellet of cholesterol placebo (7) or 2-methoxyestradiol plus cholesterol (7). Age matched controls underwent oophorectomy only (8). After 4 weeks the bladders of mice with partial bladder outlet obstruction and of unobstructed animals were harvested. Bladder sections (5 µm) were immunostained for Hypoxyprobe™-1, glucose transporter 1 and hypoxia inducible factor-1α. Real-time polymerase chain reaction was performed for hypoxia inducible factor-1α and lysyl oxidase. Statistical analysis was performed using 1-way ANOVA and the Wilcoxon rank sum test. RESULTS: Immunostaining for glucose transporter 1 and Hypoxyprobe-1 revealed the presence of tissue hypoxia after partial bladder outlet obstruction. Immunostaining and real-time polymerase chain reaction demonstrated the up-regulation of hypoxia inducible factor-1α in mice after partial bladder outlet obstruction compared to controls (p = 0.0394). Although not statistically significant, a trend toward lower gene expression of hypoxia inducible factor-1α was seen in mice receiving 2-methoxyestradiol compared to placebo (p = 0.0625). Compared to placebo, 2-methoxyestradiol treatment increased lysyl oxidase expression (p = 0.007). CONCLUSIONS: Murine partial bladder outlet obstruction resulted in hypoxia and up-regulation of the hypoxia inducible factor-1 pathway. Subcutaneous 2-methoxyestradiol administration attenuated this response and may be a viable tool to study the role of hypoxia after partial bladder outlet obstruction.

Urodynamic testing in children: indications, technique, interpretation and significance.

PURPOSE: Urodynamic studies in children have been performed with increasing frequency as the techniques, reproducibility and reliability of the testing have been refined in the last quarter century. Children of all ages and with a variety of comorbidities are now often referred for urodynamic testing to evaluate and understand the causes of incontinence and/or persistence of lower urinary tract symptoms, as well as to appropriately define and evaluate treatment regimens. MATERIALS AND METHODS: We performed a MEDLINE® search for relevant articles on urinary tract dysfunction, neurogenic bladder and urodynamic studies in the pediatric population. We also included 3 major textbooks that addressed the subject matter. RESULTS: We review the current indications for urodynamic studies in children with nonneurogenic and neurogenic bladder dysfunction. We summarize the components and techniques of the current practice of urodynamic studies in the pediatric population, and explain how to identify abnormal results. CONCLUSIONS: The use of urodynamic studies in pediatrics has become almost mandatory for the effective management of severe or therapy resistant urinary tract abnormalities. This review may be used as a guideline for the appropriate application of urodynamics in this patient population.

Bone marrow-derived mesenchymal stem cells: current and future applications in the urinary bladder.

Mesenchymal stem cells can be isolated from almost any adult tissue. In this paper we focus on bone marrow-derived mesenchymal stem cells which have captured the interest of researchers since their introduction because of the promising potential of tissue regeneration and repair. They are known for their ability to self-renew and differentiate into diverse lineages while maintaining low immunogenicity. The exact mechanisms behind how these cells work still remain unclear, and there is a continuing shift in the paradigms that support them. There has been extensive research in multiple organ systems; however, the genitorurinary system has been vastly underrepresented. This article discusses the background behind bone marrow-derived mesenchymal stem cells and they are currently being applied to the urinary bladder in the realm of tissue engineering. We also postulate on their future applications based on the current literature in other organ systems.

Robotic-assisted laparoscopic cryo-partial nephrectomy: a novel technique using cryoablation in lieu of hilar clamping in a porcine model.

Laparoscopic and robotic-assisted partial nephrectomy has become an increasingly viable approach for the resection of renal tumors. There are several technical limitations in performing laparoscopic partial nephrectomy, the most significant being the inability to easily obtain cold ischemia which allows for an extended operative time. In this study, we evaluated the feasibility and efficacy of cryoablation as an alternative to hilar clamping to maintain hemostasis during robotic-assisted laparoscopic partial nephrectomy in a porcine model. Twelve female swine underwent nine open and eight robotic-assisted laparoscopic partial nephrectomies using modified cryoablative methods to create hemostasis. Renal perfusion imaged with indocyanine green (ICG) and histological analysis was assessed immediately after the procedure and at 3 weeks post-operatively. With two freeze/thaw cycles, all nine open and eight robotic-assisted laparoscopic partial nephrectomies were successfully completed without the need for hilar clamping. The mean blood loss for the open and robotic-assisted groups was 230.6 and 99.4 ml, respectively. In all cases, maintenance of renal perfusion was confirmed by the presence of a renal pulse and intraoperative ICG imaging immediately and 3 weeks post-operatively. The histological anatomy was well preserved in the resected segment following cryo-resection. After 21 days following cryo-resection, histological analysis demonstrated normal viable tissue with minimal scarring in the remaining kidney. The use of cryoablation created a zone of hemostasis without compromising the vascularity of the remaining kidney, while preserving the renal cytoarchitecture of the segment remove for pathological analysis. Further studies will help to delineate its usefulness in laparoscopic partial nephrectomy.

Biofeedback training for lower urinary tract symptoms: factors affecting efficacy.

PURPOSE: Biofeedback therapy is a valuable modality in children with dysfunctional voiding. However, it is unclear what factors contribute to the outcome. To define who may or may not benefit from biofeedback therapy we reviewed our experience with this treatment. MATERIALS AND METHODS: We retrospectively reviewed the charts of 77 children referred between July 2005 and September 2008 for biofeedback therapy. An MR 20 Synergy trainer (Prometheus Group, Dover, New Hampshire) provided nonanimated and animated biofeedback. Uroflowmetry was performed at the start and end of each session. A total of 67 females and 10 males with a mean age of 9.0 years (range 4.8 to 18.2) comprised the cohort group. The primary referral diagnosis was nonfebrile urinary tract infection in 52 patients (67.5%), daytime and nighttime wetting in 47 (61%), voiding postponement in 14 (18.2%) and daytime incontinence in 10 (13%). Children were categorized by an outcome of success, improvement or failure. Results were analyzed using the chi-square, Fisher exact probability and Student t tests. RESULTS: Success, improvement and failure were achieved in 22 (26.8%), 29 (37.7%) and 26 cases (33.7%), respectively. Age and gender were not statistically significant predictors of outcome. A median of 3.0 sessions (range 1 to 8) was administered. Children with 3 or greater sessions were more likely to succeed (p <0.005). The improvement in urinary tract infections was statistically significant (p <0.001). Of 37 children 20 (54%) transformed a staccato voiding pattern to a normal one on uroflowmetry. CONCLUSIONS: Biofeedback therapy can be effective in children with dysfunctional voiding and urinary tract infection. Children with a staccato voiding pattern may require a minimum of 3 visits to improve the voiding pattern. Children who complete 3 sessions are more likely to succeed.