Inhibition of hypoxia-inducible factor-prolyl hydroxylation protects from cyclophosphamide-induced bladder injury and urinary dysfunction.

Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Activation of the oxygen-regulated hypoxia-inducible factor (HIF) pathway has been shown to protect mucosal membranes by increasing the expression of cytoprotective genes and by suppressing inflammation. The activity of HIF is controlled by prolyl hydroxylase domain (PHD) dioxygenases, which have been exploited as therapeutic targets for the treatment of anemia of chronic kidney disease. Here, we established a mouse model of acute cyclophosphamide (CYP)-induced blood-urine barrier disruption associated with inflammation and severe urinary dysfunction to investigate the HIF-PHD axis in inflammatory bladder injury. We found that systemic administration of dimethyloxalylglycine or molidustat, two small-molecule inhibitors of HIF-prolyl hydroxylases, profoundly mitigated CYP-induced bladder injury and inflammation as assessed by morphological analysis of transmural edema and urothelial integrity and by measuring tissue cytokine expression. Void spot analysis to examine bladder function quantitatively demonstrated that HIF-prolyl hydroxylase inhibitor administration normalized micturition patterns and protected against CYP-induced alteration of urinary frequency and micturition patterns. Our study highlights the therapeutic potential of HIF-activating small-molecule compounds for the prevention or therapy of bladder injury and urinary dysfunction due to blood-urine barrier disruption.NEW & NOTEWORTHY Disruption of the blood-urine barrier can result in acute or chronic inflammatory bladder injury. Here, we demonstrate that pharmacological inhibition of hypoxia-inducible factor (HIF)-prolyl hydroxylation prevented bladder injury and protected from urinary dysfunction in a mouse model of cyclophosphamide-induced disruption of the blood-urine barrier. Our study highlights a potential role for HIF-activating small-molecule compounds in the prevention or therapy of bladder injury and urinary dysfunction and provides a rationale for future clinical studies.

Renal Transplants Due to Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) Have Better Graft Survival Than Non-CAKUT Controls: Analysis of Over 10,000 Patients.

OBJECTIVE: To determine whether graft survival for patients with congenital anomalies of the kidney and urinary tract (CAKUT) is impaired compared to non-CAKUT counterparts. METHODS: The United States Renal Data System (USRDS) is a national data system that has collected information about end stage renal disease (ESRD) and renal transplantation since 1995. We identified 10,635 first-time renal transplant patients with ESRD attributed to a CAKUT diagnosis transplanted between 1995 and 2018, with follow-up of 7.9 ± 5.8 years. We matched 1:1 with non-CAKUT transplant recipients, using age at transplant, sex, race, year of transplant, and donor-type. We compared renal transplant death-censored graft survival between CAKUT vs non-CAKUT controls, with further stratification for age at transplant and lower urinary tract malformations (LUTM) vs upper urinary tract malformations (UUTM). RESULTS: Graft survival was better in CAKUT patients with a 5-year survival of 83.3% vs 79.3% (P< .001), and CAKUT status infers a hazard ratio of 0.878 for graft failure on multivariable analysis with Cox regression. Favorability of CAKUT status persisted when stratifying for both pediatric (80.3 vs 77.6% P< .001) and adult (84.5 vs 81.4% P< .001) age groups. Looking within the CAKUT population: comparison of LUTM to UUTM yielded no difference, implying that LUTM is not a risk factor for graft failure. Examining pediatric LUTM alone, graft survival was not better than matched non-CAKUT counterparts with 5-year graft survival of 69%-75% for LUTM adolescents. CONCLUSION: Renal transplant graft survival is better overall in CAKUT patients as opposed to non-CAKUT counterparts. Pediatric LUTM patients have similar graft survival to controls.

New-onset ESRD secondary to reflux nephropathy has decreased in incidence in the United States.

INTRODUCTION AND OBJECTIVE: Vesicoureteral reflux (VUR) has been associated with the development and progression of reflux nephropathy (RN). Management of VUR has become more conservative over time as therapies have not been reliably proven to prevent renal scarring. We sought to examine the incidence of end stage renal disease (ESRD) due to RN over recent decades in the United States. STUDY DESIGN: The United States Renal Data System (USRDS) is a national data system that collects information about chronic kidney disease and ESRD. Since 1995, the USRDS has mandated that all dialysis centers enroll and submit data on new-onset ESRD patients. Of the over 2.5 million patients enrolled since 1996, 7314 were enrolled with a diagnosis code for RN as the primary cause of ESRD. We examined the trends seen in this patient population from 1996 to 2014 and used US census data to calculate incidence. RESULTS: The incidence of patients with new-onset ESRD attributed primarily to RN saw a steady decrease over time: from 1.9 per million in 1996 to 0.6 per million in the US population in 2014 (exp(B) = 0.941, p < 0.001). 58.8% of the patients were female, 87.4% white. The mean age at the time of ESRD onset was 47 years (IQR 30-65) and this did not significantly vary over the period (P > 0.05). When comparing pediatric new-onset ESRD to adult-onset, a non-significant trend (p = 0.093) was seen with a decrease in incidence of adult ESRD, but a relatively stable incidence of pediatric ESRD (mean age 12, incidence 0.2-0.6 cases per million US children/year). 44.5% of patients received renal transplantation at a mean age of 36 years, 18.9 months (IQR 5-40) after ESRD diagnosis. The mean age of mortality was 62 years old (IQR 50-76), and 5-year survival after RN ESRD diagnosis was 65.8%. DISCUSSION: As with any public database study, our findings may be limited by disease coding or reporting practices. Medical and surgical management trends practiced since the 1960s may have contributed to a decrease in the incidence of ESRD primarily attributed to RN in the United States between 1996 and 2014. Our findings may also reflect changes in diagnostic practices. CONCLUSIONS: ESRD attributed primarily to RN has gradually decreased in incidence in the United States between 1996 and 2014, but the age of ESRD onset has been unchanged.

Prospective Evaluation of Sacral Neuromodulation in Children: Outcomes and Urodynamic Predictors of Success.

PURPOSE: Sacral neuromodulation has been demonstrated to improve refractory bowel bladder dysfunction in children. The purpose of the current study was to determine whether results are durable in children after longer followup, whether children with a lower body mass index are at risk for device failure and whether pretreatment urodynamic evaluation can predict posttreatment outcome. MATERIALS AND METHODS: Pediatric patients with refractory bowel bladder dysfunction were enrolled following informed consent and followed prospectively. All patients underwent preoperative videourodynamic evaluation and a 2-stage implantation procedure. Validated questionnaires were used to assess symptom severity and quality of life. Complications were analyzed with regard to treatment required and patient body mass index. RESULTS: During 45 months 30 patients were enrolled. Median age was 8.3 years at enrollment. Median followup was 14.8 months. Patients had significant improvement in quality of life and symptom scores, which persisted at the most recent followup. Patients who had uninhibited detrusor contractions on preoperative urodynamic assessment had significantly greater improvement in symptoms. Of the patients 23% had a complication requiring reoperation, most commonly neurostimulator lead breakage in those with a significantly lower body mass index. CONCLUSIONS: Sacral neuromodulation significantly improves quality of life and symptom severity in children with refractory bowel bladder dysfunction. Children gain greater benefit if they show uninhibited bladder contractions on preoperative urodynamic evaluation. Children have a high rate of lead breakage requiring operative revision, which was seen after minor trauma in those with a lower body mass index.

Diagnosis of constipation does not correlate with trans-abdominal ultrasound of rectal distention.

INTRODUCTION: Constipation has been shown to have a significant impact on lower urinary tract symptoms (LUTS) in children, and treatment of constipation in children with bowel bladder dysfunction (BBD) has been shown to improve or completely resolve LUTS in many cases. Recent studies utilizing trans-abdominal ultrasound (US) to assess stool burden have correlated diagnosis of constipation with US appearance of rectal stool. An US scoring tool was published in 2008 to assess stool burden, showing linear correlation with constipation severity by symptom questionnaire in an outpatient pediatric constipation clinic population. We hypothesized that this US scoring tool would correlate with constipation symptoms in our outpatient pediatric urology population. METHODS: In 2010, our pediatric urology outpatient clinic began administering a previously published validated BBD questionnaire to new toilet-trained patients, containing three questions addressing bowel function. Patients in our clinic undergoing trans-abdominal US of the bladder also have assessment of their stool burden by the previously published US scoring tool. We retrospectively reviewed patient charts beginning in June 2013 who had undergone trans-abdominal US of the bladder, gathering data on the first 100 patients with a complete BBD questionnaire and a completed stool burden US scoring tool. RESULTS: Chart review of 272 consecutive patients was required to enroll 100 patients with a completed US scoring of stool burden and a completed BBD questionnaire. Of these 272 patients, 225 (82%) had a complete scoring of stool burden during their US examination. BBD questionnaires were complete in 107 of 272 patients (39%). Median patient age was 8.2 years, with 69% of patients being female. The most common diagnosis was incontinence or bladder dysfunction (41%). Only one patient (1%) had constipation as the primary diagnosis for their visit. Linear regression analysis showed no correlation of US score to patient reported frequency of bowel movement, frequency of hard stool, frequency of fecal incontinence, or all three symptoms combined. When investigating the subgroup of patients who had diagnoses of BBD/incontinence, this group was seen to have higher mean symptom scores than the entire cohort as a whole, but US scores were still widely variable and again did not correlate with symptom scores. CONCLUSION: US examination has previously been shown to correlate with symptom severity for children with chronic constipation in a pediatric constipation clinic setting. However, in a pediatric urology outpatient clinic setting at our institution, US examination did not correlate with patient reported symptoms.

Bullying and lower urinary tract symptoms: why the pediatric urologist should care about school bullying.

PURPOSE: Bullying has become a social plague associated with various deleterious outcomes. We hypothesized that pediatric lower urinary tract symptoms could be associated with exposure to bullying. MATERIALS AND METHODS: We assessed exposure to school bullying via the Setting the Record Straight bullying questionnaire in children 8 to 11 years old being evaluated for lower urinary tract symptoms at our pediatric urology clinic. Lower urinary tract symptoms were quantified with the Vancouver Symptom Score. Children 8 to 11 years old presenting for pediatric well visits also completed the questionnaires. Linear regression assessed the relationship between Vancouver Symptom Score and bullying score. Categorical variables were compared by chi-square test, while continuous variables were compared using the Student t-test. RESULTS: A total of 113 children at the urology clinic and 63 children in the primary care setting consented to participate. There were significant differences between the 2 populations, including gender and race, with significantly more perpetrators of bullying in the primary care group (7.9% vs 0.9%, p = 0.02). When looking specifically at the urology group, there was a significant association between Vancouver Symptom Score and self-perceived (p <0.001) and peer perceived (p <0.001) victimization scores. In the primary care group there was also a significant association between Vancouver Symptom Score and self-perceived (p = 0.01) and peer perceived (p = 0.001) bullying perpetrator scores. Of children seen at the primary care office 33% had a significant Vancouver Symptom Score. CONCLUSIONS: Although bullying exposure is multifactorial, we found that Vancouver Symptom Score can be associated with bullying victimization and perpetrator scores.

Robotic-assisted partial nephrectomy in duplicated collecting systems in the pediatric population: techniques and outcomes.

OBJECTIVE: We present our experience with pediatric robotic-assisted laparoscopic partial nephrectomy of a nonfunctioning moiety in a duplicated system (RALPN), comparing techniques and outcomes with those previously reported in the literature. To our knowledge, this is the largest series of this surgical procedure to date. PATIENTS AND METHODS: We retrospectively reviewed all pediatric patients at our institution that had undergone RALPN from 2006 to 2012. RESULTS: Twenty-one patients underwent RALPN between 2006 and 2012. Mean patient age was 4.1 years. Mean operative time was 301 min. Mean estimated blood loss was 36 ml. Mean length of stay was 38 h. The majority of cases were performed with three laparoscopic ports. At initial follow-up ultrasound 6/21 (29%) demonstrated a fluid collection. The majority of these collections occurred in cases where the resection defect was not closed intraoperatively (42% of cases vs. 11% of cases). All fluid collections were asymptomatic and managed conservatively. CONCLUSION: RALPN is associated with low complication rates. The robotic system allows for the use of only two small robotic working ports in most cases. Postoperative fluid collections may be prevented by formal closure of the polar defect, but fluid collections that do occur can be followed conservatively.

Kinetic isotope effects support the twisted amide mechanism of Pin1 peptidyl-prolyl isomerase.

The Pin1 peptidyl-prolyl isomerase catalyzes isomerization of pSer/pThr-Pro motifs in regulating the cell cycle. Peptide substrates, Ac-Phe-Phe-phosphoSer-Pro-Arg-p-nitroaniline, were synthesized in unlabeled form, and with deuterium-labeled Ser-d3 and Pro-d7 amino acids. Kinetic data were collected as a function of Pin1 concentration to measure kinetic isotope effects (KIEs) on catalytic efficiency (kcat/Km). The normal secondary (2°) KIE value measured for the Ser-d3 substrate (kH/kD = 1.6 ± 0.2) indicates that the serine carbonyl does not rehybridize from sp(2) to sp(3) in the rate-determining step, ruling out a nucleophilic addition mechanism. The normal 2° KIE can be explained by hyperconjugation between Ser α-C-H/D and C═O and release of steric strain upon rotation of the amide bond from cis to syn-exo. The inverse 2° KIE value (kH/kD = 0.86 ± 0.08) measured for the Pro-d7 substrate indicates rehybridization of the prolyl nitrogen from sp(2) to sp(3) during the rate-limiting step of isomerization. No solvent kinetic isotope was measured by NMR exchange spectroscopy (kH2O/kD2O = 0.92 ± 0.12), indicating little or no involvement of exchangeable protons in the mechanism. These results support the formation of a simple twisted amide transition state as the mechanism for peptidyl prolyl isomerization catalyzed by Pin1. A model of the reaction mechanism is presented using crystal structures of Pin1 with ground state analogues and an inhibitor that resembles a twisted amide transition state.

Bladder perforation in augmentation cystoplasty during urodynamic investigation: a case report and review of the literature.

BACKGROUND: Spontaneous bladder rupture is a known complication of augmentation cystoplasty. We report the second case of bladder rupture during filling cystometry many years after bladder augmentation and the first case occurring in a patient with an autoaugmentation cystoplasty. In addition, the management and outcome for a bladder perforation in an autoaugmentation cystoplasty will be discussed. CASE: A 20-year-old male with a history of an L4 myelomeningocele underwent an autoaugmentation cystoplasty for neurogenic bladder dysfunction and decreased bladder wall compliance five years previously. He self catheterized four times daily. During filling cystometry, detrusor pressure increased to 60 cm H(2)O with 300 mL filling. Detrusor pressure then rapidly decreased to 20 cm H(2)O without evidence of external leakage. The infusion was immediately stopped and X-ray showed intraperitoneal leakage of contrast material. Serial abdominal examination demonstrated worsening abdominal distension. Exploratory laparotomy revealed a 2 cm perforation within the autoaugment portion of the bladder. CONCLUSION: An autoaugmentation cystoplasty improves bladder compliance and capacity with the use of native urothelial tissue. Although perforation after autoaugmentation has not been previously reported, caution must be used during urodynamic evaluation in patients with decreased bladder wall compliance and augmentation cystoplasty.

Transurethral placement of vaginal contraceptive device in a patient with neurogenic bladder: a case report and review of the literature.

BACKGROUND: The NuvaRing is a vaginal contraceptive device that is placed and later removed by the user herself. Incorrect placement is a possible complication and seems an increased risk in patients with spinal cord abnormalities. CASE: A 21-year-old female with a history of a T7-8 level spinal cord injury at birth and subsequent neurogenic bladder dysfunction and bladder augmentation presented with an 8 month history of suprapubic pain, right hip pain and urgency unresponsive to antibiotic therapy. Her symptoms began after her caretaker placed a NuvaRing contraceptive device, which subsequently was unable to be located. A thorough evaluation revealed a NuvaRing in the bladder. CONCLUSION: Foreign objects should be considered in patients with recurrent symptoms of cystitis which are unrelieved by antibiotic therapy. Intravaginal contraceptive rings should be used cautiously in patients with spinal cord abnormalities who require the assistance of caretakers for management of these devices.

Robot-assisted upper pole nephrectomy in adult patients with duplicated renal collecting systems.

Duplicated renal collecting systems are a common congenital anomaly, with patients usually presenting in childhood, rarely in adult life. To our knowledge, only one case of robot-assisted heminephrectomy in adults has been described. We reviewed the medical records of four adult patients with symptomatic unilateral duplicated collecting systems and nonfunctioning upper pole renal units (NFUPRU) who underwent robot-assisted laparoscopic heminephrectomy at our institutions. Heminephrectomy for NFUPRU should be approached differently than partial nephrectomy, because of complex vascular anatomy. Patients who are undergoing this procedure have brief hospital stays, minimal morbidity, preservation of renal function, and resolution of symptoms. Robot-assisted laparoscopy is well suited for this procedure because it allows improved visualization during dissection of the unique vascular anatomy as well as scaling of surgeon movements and improved ergonomics.

Clinical practice: surgical approaches to urolithiasis in children.

The incidence of urolithiasis in children is increasing. Adequate knowledge of treatment modalities and surgical options is therefore essential for every pediatrician. Surgical approaches to urolithiasis in children continue to evolve with advancements in technology and sophistication of current equipment and techniques. Perhaps the most significant development in new techniques is the advent of robotic-assisted laparoscopy. This review, for the general pediatrician, summarizes the most recent pediatric data and guidelines for surgical approaches to treatment of urolithiasis.

Serine-cis-proline and serine-trans-proline isosteres: stereoselective synthesis of (Z)- and (E)-alkene mimics by Still-Wittig and Ireland-Claisen rearrangements.

Two new amide isosteres of Ser-cis-Pro and Ser-trans-Pro dipeptides were designed and stereoselectively synthesized to be incorporated into potential inhibitors of the phosphorylation-dependent peptidylprolyl isomerase Pin1, an essential regulator of the cell cycle. The cis mimic, the (Z)-alkene isomer, was formed through the use of a Still-Wittig [2,3]-sigmatropic rearrangement, while the trans mimic, the (E)-alkene, was synthesized through the use of an Ireland-Claisen [3,3]-sigmatropic rearrangement. Starting from N-Boc-Ser(OBn)-N(OMe)Me, both mimics were synthesized in Boc-protected form suitable for peptide synthesis with an overall yield of 20% in 10 steps for the cis mimic and 13% in eight steps for the trans mimic.