Continuous Normothermic Ex Vivo Kidney Perfusion Is Superior to Brief Normothermic Perfusion Following Static Cold Storage in Donation After Circulatory Death Pig Kidney Transplantation.

Hypothermic preservation is known to cause renal graft injury, especially in donation after circulatory death (DCD) kidney transplantation. We investigated the impact of cold storage (SCS) versus short periods of normothermic ex vivo kidney perfusion (NEVKP) after SCS versus prolonged, continuous NEVKP with near avoidance of SCS on kidney function after transplantation. Following 30 min of warm ischemia, kidneys were removed from 30-kg Yorkshire pigs and preserved for 16 h with (A) 16 h SCS, (B) 15 h SCS + 1 h NEVKP, (C) 8 h SCS + 8 h NEVKP, and (D) 16 h NEVKP. After contralateral kidney resection, grafts were autotransplanted and pigs followed up for 8 days. Perfusate injury markers such as aspartate aminotransferase and lactate dehydrogenase remained low; lactate decreased significantly until end of perfusion in groups C and D (p < 0.001 and p = 0.002). Grafts in group D demonstrated significantly lower serum creatinine peak when compared to all other groups (p < 0.001) and 24-h creatinine clearance at day 3 after surgery was significantly higher (63.4 ± 19.0 mL/min) versus all other groups (p < 0.001). Histological assessment on day 8 demonstrated fewer apoptotic cells in group D (p = 0.008). In conclusion, prolonged, continuous NEVKP provides superior short-term outcomes following DCD kidney transplantation versus SCS or short additional NEVKP following SCS.

Normothermic Ex Vivo Kidney Perfusion Following Static Cold Storage-Brief, Intermediate, or Prolonged Perfusion for Optimal Renal Graft Reconditioning?

Normothermic ex vivo kidney perfusion (NEVKP) demonstrated superior results compared to hypothermic storage in donation after circulatory death (DCD) kidney transplantation. It is unknown whether an optimal perfusion time exists following hypothermic storage to allow for the recovery of renal grafts from cold ischemic injury. In a porcine model of DCD kidney autotransplantation, the impact of initial static cold storage (SCS) (8 h) followed by various periods of NEVKP recovery was investigated: group A, 8 hSCS only (control); group B, 8 hSCS + 1 hNEVKP (brief NEVKP); group C, 8 hSCS + 8 hNEVKP (intermediate NEVKP); and group D, 8 hSCS + 16 hNEVKP (prolonged NEVKP). All grafts were preserved and transplanted successfully. One animal in group D was sacrificed and excluded by postoperative day 3 due to hind limb paralysis, but demonstrated good renal function. Postoperative graft assessment during 8 days' follow-up demonstrated lowest levels of peak serum creatinine for intermediate (C) and prolonged (D) NEVKP (p = 0.027). Histological assessment on day 8 demonstrated a significant difference in tubular injury (p = 0.001), with highest values for group B. These results suggest that longer periods of NEVKP following SCS are feasible and safe for postponing surgical transplant procedure and superior to brief NEVKP, reducing the damage caused during cold ischemic storage of renal grafts.

Urethral compliance in hypospadias operated by tubularized incised urethral plate (TIP) with and without a dorsal inlay graft: an experimental controlled study.

OBJECTIVE: Abnormal uroflowmetries are common after tubularized incised plate urethroplasties (TIP), perhaps due to low compliance. We hypothesized that (1) abnormal uroflowmetries after TIP might be caused by segmental lower compliance; (2) by adding a graft to the raw area in the incised plate (TIPG), compliance might be improved by preventing secondary intention healing of the dorsal incision. METHODS: A standardized penectomy was performed in 27 adult male rabbits: 9 normal non-operated controls (G1), 6 weeks after TIP (G2: n = 9) or TIPG (G3: n = 9). A standardized isolated segment (including the whole urethroplasty in G1 and G2) was progressively distended with air (1, 2 and 3 ml) in the 3 groups. The respective intraluminal pressures were measured with a tensiometer. RESULTS: Pressure measurements were feasible and reproducible for this model. Mean pressures tended to be higher in the experimental groups (G1: 59.7 mmHg vs. G2: 79.6 mmHg vs. G3: 100.1 mmHg for 1 ml injections; G1: 233.1 mmHg vs. G2: 241 mmHg vs. G3: 308.4 mmHg for 2 ml injections and G1: 457.3 mmHg vs. G2: 429 mmHg vs. G3: 520 mmHg for 3 ml injections) without reaching the statistical significance. CONCLUSION: In this model, the elasticity of the TIP or TIPG neourethras tended to be reduced when compared to controls. The placement of an inlay graft on the dorsal incised area did not increase the compliance. This model allows the measurement of segmental intraluminal urethral pressures generated by controlled air distension and may be a useful tool to evaluate the experimental urethroplasty models.

The orchestration of gene expression and the editing role of microRNA.

In this short educational communication the ESPU Research Committee presents the role of non-coding RNA and how these can affect gene expression. In particular we discuss the role of microRNA on post transcriptional changes and how these may cause pathological conditions within Pediatric Urology and how microRNA could be useful in future clinical practice.

COVID-19 and research in pediatric urology.

COVID-19 began in December 2019 then spread worldwide. Providers, including pediatric urologists, had to adapt their clinical processes, and many non-covid research activities were suspended. COVID-19 impacts how research is financed, performed, and published, and is itself the subject of intense research. We present current research and publications specifically related to the urinary tract and the pediatric population.

Fetal exposure to polybrominated diphenyl ethers and the risk of hypospadias: focus on the congeners involved.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and their endocrine-disrupting properties have focused growing attention regarding their teratogenic potential. We have recently documented that mothers of children born with hypospadias had been exposed to statistically higher levels of PBDE during pregnancy than mothers of healthy controls. However, it is not known which congeners of PBDE are associated with this putative teratogenic effect. OBJECTIVES: To identify PBDE congeners associated with increased risk for hypospadias. STUDY METHODS: Hair samples from mothers were analyzed and compared between hypospadias cases and healthy controls for eight PBDE congeners using gas chromatography mass spectrometry (GC/MS). Polybrominated diphenyl ether levels were measured in the 0- to 3-cm segment closest to the skull of maternal hair as a proxy for in utero exposure of mothers who lived in the same environment for the duration of their pregnancy. RESULTS: Median maternal hair levels of five PBDE congeners (28, 47, 99, 153, and 154) and of total PBDE (∑PBDE) were significantly higher among mothers of infants with hypospadias (n = 152) than among controls (n = 64). Apparent greater differences in the lower brominated congeners, especially in BDE-47 and BDE-99, may be due to the fact that they had been used in larger amounts, and their persistence properties confer longer exposure. CONCLUSIONS: The majority of the lower brominated PBDE congeners measured in maternal hair exhibited higher PBDE body burden during pregnancy in mothers of infants who were born with hypospadias.

Accuracy of point-of-care ultrasound by pediatric emergency physicians for testicular torsion.

INTRODUCTION: Acute scrotum is a common presentation to the pediatric emergency department, and ultrasound is frequently used to narrow the differential diagnosis. Point-of-care ultrasound (POCUS) is increasingly used by urologists and emergency physicians and could potentially be used to detect pediatric testicular torsion. OBJECTIVES: This study aimed to determine the accuracy of POCUS by pediatric emergency physicians in diagnosing testicular torsion and the agreement between point-of-care ultrasound and final diagnosis for other causes of acute scrotum. STUDY DESIGN: A chart review of patients presenting to the study emergency department who received POCUS by a pediatric emergency physician, as well as radiology department ultrasound and/or surgery, was performed. Charts were reviewed for POCUS diagnoses, final diagnoses, and imaging time metrics. RESULTS: A total of 120 patients met study criteria, with 12 cases of testicular torsion. The diagnostic accuracy of POCUS for testicular torsion is described in the summary table. For all causes of acute scrotum, point-of-care ultrasound agreed with final diagnosis in 70% (95% confidence interval [CI] 62-78%) of cases, and more experienced point-of-care ultrasound users displayed higher agreement with final diagnosis. Point-of-care ultrasound results were generated a median of 73 min (Q1 = 51, Q3 = 112) before radiology department ultrasound results. DISCUSSION: Scrotal POCUS performed by pediatric emergency physicians appears to be an accurate tool to detect testicular torsion in children with acute scrotum and saves time compared with radiology ultrasound. The study results may not be generalizable to hospitals without a multidisciplinary POCUS system for quality assurance and image sharing. Future work on POCUS for acute scrotum should investigate its impact on patient outcomes, cost-effectiveness, and family satisfaction. CONCLUSION: Point-of-care ultrasound by pediatric emergency physicians is accurate for detecting testicular torsion in children with acute scrotum and could expedite diagnosis of this time-sensitive condition.

EBM II: How to perform a literature search.

The present article is a second part related to evidence based medicine (EBM) in a series of five by the European society for paediatric urology (ESPU) research committee. It will present the different databases/search engines available to clinicians and researchers and describe strategies to focus the search to one's particular needs. Indeed, databases/search engines used and search strategy should vary according to the goal of the research. If the aim is to address a clinical problem, the search should allow to identify a small number of most pertinent articles (high specificity); if the search is for research purposes, instead, it should ensure no meaningful articles are overlooked (high sensitivity).

Evidence-based medicine 1: Background.

The Research Committee of the European Society of Pediatric Urology will present a series of short educational communications related to evidence-based medicine. The aim of the series is to emphasize the importance of grading evidence, thereby determining the best clinical practice for patients. The goal of this series is to guide the clinician in using tools for setting up a clinical question, finding appropriate information, searching appropriate databases, and evaluating the results in relation to the patient in mind. This first part will serve as an introduction or background. Following publications will cover the topics of hierarchy of evidence, information acquisition, clinical appraisal tools, and applications in clinical practice [3].

Evidence Based Medicine IV: how to find an evidence-based answer to a clinical question? Make a critically appraised topic!

This manuscript is the fourth in a five part series related to evidence based medicine (EBM) provided by the European society of pediatric urology (ESPU) research committee. It will present a way to come to a quick and critical appraisal of available evidence on a specific topic: a CAT (critically appraised topic). The way how to write a cat is described for interventions to be compared to a control group, and for other, more generalized clinical questions. While systematic reviews provide a throughout overview of all evidence available, a CAT provides a shorter way to come to quick insights based on EBM.

Evidence-based medicine III: level of evidence.

The present article is the third installment in a five-part series related to evidence-based medicine (EBM) provided by the European Society for Paediatric Urology Research Committee. It will present the different levels of evidence (i.e. systematic review, randomized controlled trial, cohort study) available to clinicians and researchers and describe the strengths of each study type. While EBM provides a valuable construct to aid in medical decision-making, it remains imperative that this information be interpreted and applied in the clinical context with a good dose of common sense.

Modified staged repair of bladder exstrophy: a strategy to prevent penile ischemia while maintaining advantage of the complete primary repair of bladder exstrophy.

INTRODUCTION: Penile ischemic injury is a reported catastrophic complication after complete primary repair of exstrophy (CPRE). Aiming to improve the bladder exstrophy-epispadias repair outcomes, the study institution adopted a modified staged exstrophy repair to incorporate the advantages of CPRE by avoiding concurrent epispadias repair and adding bilateral ureteral re-implantation and bladder neck tailoring (staged repair of bladder exstrophy with bilateral ureteral re-implantation [SRBE-BUR]) at the initial repair. It was hypothesized that such modifications minimize penile complications and prevent upper tract deterioration while enhancing bladder resistance and consequent capacity. Here, a comparative series of outcomes between CPRE and SRBE-BUR is reported. METHODS: A retrospective cohort study including all exstrophy-epispadias male neonates managed in the study institution from January 2000 to December 2014 was performed. Patients were divided into those who underwent CPRE-BUR (group 1) and SRBE-BUR (group 2) (Figure). Baseline characteristics, peri-operative data, and long-term surgical outcomes were collected and analyzed for between-group comparison. Fisher exact and Mann-Whitney U tests were performed for statistical analysis. RESULTS: A total of 21 eligible patients were included: 10 in group 1 and 11 in group 2. Baseline characteristics were comparable. Two patients in group 1 had intra-operative penile ischemic injury (one with subsequent penile tissue loss), whereas none of the group 2 patients had intra-operative complications. No significant difference between the groups was noted for operative time; however, significantly lesser blood loss was noted in group 2. Comparable long-term surgical outcomes such as additional surgical intervention, urinary continence, bladder capacity, vesicoureteral reflux, hydronephrosis and recurrent urinary tract infections (UTIs) were noted. In addition, although subjective, better penile length and cosmesis were achieved by staging the repair (Figure). CONCLUSION: The SRBE with bilateral ureteral re-implantation is a safe alternative for the repair of the exstrophy-epispadias repair as it prevents the catastrophic complication of penile tissue loss, while having comparable long-term outcomes with the CPRE. Delaying epispadias repair avoids penile injury besides possible improvement of its overall cosmesis.

Stent-related complications after hypospadias repair: a prospective trial comparing Silastic tubing and Koyle urethral stents.

INTRODUCTION: There is a paucity of data comparing urethral stents after hypospadias repair. The aim of this study is to compare Silastic tubing vs Koyle stents (Cook Medical), addressing outcomes related to stent-related complications, added visits to healthcare providers in the early postoperative period, and postoperative complications at clinic follow-up. MATERIALS AND METHODS: Following an alternate week allocation, 150 patients were prospectively assigned to have Silastic tubes (n = 76) and Koyle stents (n = 74) after hypospadias repair. Exclusion criteria included fistula repairs, drainage via alternative catheter, or stentless repairs. Silastic tubes were secured with 5-0 Prolene and removed during a planned clinic visit. Koyle stents were secured with 7-0 PDS and left to fall out spontaneously. Questionnaires capturing postoperative outcomes were completed. RESULTS AND DISCUSSION: Median age was 13 and 11 months in the Silastic and Koyle stent groups, respectively (P = 0.48). There was no statistically significant difference in hypospadias location. Blockage/kinking of stents occurred in 8% (n = 6) of the Silastic and 9% (n = 7) Koyle stent groups, P = 0.78. Although follow-up was short, there was no difference in fistula rate among the Silastic (21%, n = 14) versus Koyle stent group (17%, n = 11), P = 0.66. There was a twofold higher rate of emergency department (ED) visits in the Silastic (32%, n = 24) versus Koyle stent group (16%, n = 12), P = 0.03. Half of ED visits in the Silastic group were related to stents falling out before planned removal. The authors propose that Silastic stents falling out before the removal date may have led to increased parental anxiety and thus a visit to the ED. With improved parental education, the authors propose that many of these visits may have been preventable. CONCLUSIONS: There were no significant differences in stent-related complications or fistula rate between the Silastic and Koyle stent groups. Although there were a twofold higher number of visits to the ED in the Silastic stent group, the authors propose that this was due to parental education rather than the stent itself.

Postoperative pain and analgesia administration in children after urological outpatient procedures.

INTRODUCTION: There are limited data about pain patterns, analgesic requirements and factors predicting opioid requirements of children undergoing outpatient urologic surgery. This prospective study aimed to assess recovery profiles and pain medication requirements. METHODS: Patients between 6 months and 12 years of age were recruited prospectively between December 2013 and June 2014. Demographic and operative characteristics were collected. Following discharge home, the parents were asked to administer both acetaminophen and ibuprofen Q6H at a weight-adjusted dose, based on a schedule, until the end of postoperative day 2, and to administer the medication as required on postoperative day 3. Pain severity was recorded using validated pain scores (Face, Legs, Activity, Cry, Consolability/Parents' Postoperative Pain Measurement). A morphine prescription was provided for breakthrough pain. A Likert scale was used to assess parent's satisfaction with the pain management. RESULTS: A total of 249 patients were recruited, 111 patients (45%) returned appropriately completed surveys and were included in the final analysis. Mean age was 44.1 months (SD = 37.3). The performed procedures were orchidopexy (31), hypospadias repair (26), hernia/hydrocele repair (15), Fowler-Stephens procedure (13), meatoplasty (7), phalloplasty (4), scrotoplasty (1), circumcision (7), and diagnostic laparoscopy (5). After discharge home 17 patients (15.3%) received morphine. Mean utilization of non-opioid analgesia was 79% on postoperative day 1, 67% on day 2, 36% on day 3, and 2% on day 4. Parental satisfaction was high (92.0% satisfied/very satisfied). No patient, anaesthetic or surgical factors were associated with opioid use or prolonged need for postoperative analgesia. CONCLUSION: The combination of scheduled non-opioid medications for maintenance and opioids for breakthrough pain provided satisfactory pain control after outpatient urologic surgery in children. There were no specific patient, anesthetic or surgical factors that predicted postoperative opioid requirements.

c-Ha-ras-I oncogene-induced differentiation and natural killer cell resistance in a human colorectal carcinoma cell line.

Natural killer (NK) activity is primarily a peripheral blood function of a lymphocyte population capable of spontaneous lysis of many transformed and metastatic targets. However, NK-susceptible targets tend to be relatively poorly differentiated. We have previously shown that poorly differentiated human colorectal carcinoma are lysed by NK cells. Well-differentiated and chemically differentiated colorectal carcinomas are insensitive to NK lysis. The present study demonstrates that transfection of the c-Ha-ras-I oncogene into a poorly differentiated colorectal carcinoma cell line also renders it NK resistant. This resistance is accompanied by a more differentiated colorectal carcinoma phenotype. Two ras-transfected lines (Clone-A-5 and Clone-A-4) showed a 30-66% decrease in susceptibility to NK lysis as compared to the parental line in standard cytotoxicity assays. The resistance of these transfectants was strictly dependent on expression of the activated p21, the H-ras protein product. Studies to assess the integrity of the initial binding step in NK lysis showed a significant decrease in the ability of these transfectants to form conjugates with fresh NK cells. It is likely that transfection with c-Ha-ras-I has selectively modulated critical NK target recognition structures.

Proximal hypospadias: A persistent challenge. Single institution outcome analysis of three surgical techniques over a 10-year period.

INTRODUCTION: The optimal treatment of proximal hypospadias remains controversial. Several techniques have been described, but the best approach remains unsettled. OBJECTIVE: To evaluate and compare the complication rates of proximal hypospadias with and without ventral curvature (VC), according to three different surgical techniques: tubularized incised plate (TIP) uretroplasty, dorsal inlay graft TIP (DIG), and staged preputial repair (SR). It was hypothesized that SR performs better than TIP and DIG for proximal hypospadias. METHODS: Single-center, retrospective chart review of all patients with primary proximal hypospadias reconstructed between 2003 and 2013. The DIG was selectively employed in cases with narrow urethral plate (UP) and deficient spongiosum. Extensive urethral plate (UP) mobilization (UPM), dorsal plication (DP) and/or deep transverse incisions of tunica albuginea (DTITA) were selectively performed when attempting to spare transecting the UP. Division of UP and SR was favored in cases with severe VC (>50°), which was often concurrently managed with DTITA if intrinsic curvature was present. For SR, tubularization of the graft was performed 6 months later. RESULTS: A total of 140 patients were included. Tubularized incised plate (TIP), DIG, and SR techniques were performed in 57, 23, and 60 patients, respectively. The TIP and DIG techniques achieved similar success rates, although DIG was performed in cases of narrow and spongiosum-deficient plates. Reoperation rates with TIP and DIG techniques was 52.6% and 52.1% (NS). Urethro-cutaneous fistulas were seen in 31.5% and 13% of TIP and DIG techniques, respectively. Staged repair accomplished better results than both TIP and DIG techniques, despite being performed in the most unfavorable cases (reoperation rate 28%). After technical modifications, the DIG technique achieved similar outcomes of SR. CONCLUSIONS: Proximal hypospadias remains challenging, regardless of the technique utilized for its repair. Urethro-cutaneous fistulas were more commonly seen after long TIP repairs. Approximately half of the patients undergoing long TIP and DIG procedures needed re-intervention, although the percentage decreased significantly with late modifications in the DIG group. Recurrence of VC after TIP and DIG techniques seemed to be a significant and under-reported complication. Staged repairs, despite being performed for the most severe cases, resulted in overall better outcomes.

Natural killer sensitivity of colorectal carcinoma targets. Correlation with degree of differentiation.

Lymphocytes with natural killer (NK) ability recognize a wide range of target cells; however, the mediators of specific target recognition are still largely unknown. Despite the diversity of the NK target repertoire, it is typified by cells of relatively immature phenotype. The purpose of this study was to determine if colorectal carcinoma (CRC) targets were sensitive to spontaneous lysis by fresh human NK effector cells and to observe the role of CRC differentiation in this process. Results demonstrated that poorly differentiated CRC targets were susceptible to NK-mediated lysis whereas CRC targets with more differentiated structure were NK resistant. In addition, chemical induction of a more mature CRC phenotype confers NK resistance on a previously NK-susceptible target. This maturation-related modulation of NK sensitivity can provide a model with which to further study interaction between NK cells and CRC targets.