Patricia S. Cho

Aerosolized GM-CSF ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice

Surfactant proteins and phospholipids accumulate in the alveolar spaces and lung tissues of mice deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF), with pathological findings resembling the histology seen in the human disease pulmonary alveolar proteinosis (PAP). Previous metabolic studies in GM-CSF-deficient [GM(-/-)] mice indicated that defects in surfactant clearance cause the surfactant accumulation in PAP. In the present study, GM(-/-) mice were treated daily or weekly with recombinant mouse GM-CSF by aerosol inhalation or intraperitoneal injection for 4-5 wk. Lung histology, alveolar macrophage differentiation, and surfactant protein B immunostaining returned toward normal levels in the GM-CSF aerosol-treated mice. Alveolar and lung tissue saturated phosphatidylcholine and surfactant protein B concentrations were significantly decreased after treatment with aerosolized GM-CSF. Cessation of aerosolized GM-CSF for 5 wk resulted in increased saturated phosphatidylcholine pool sizes that returned to pretreatment levels. In contrast, PAP did not improve in GM(-/-) mice treated daily for 5 wk with larger doses of systemic GM-CSF. Aerosolized GM-CSF improved PAP in the GM(-/-) mice, demonstrating that surfactant homeostasis can be influenced by local administration of GM-CSF to the respiratory tract.Surfactant proteins and phospholipids accumulate in the alveolar spaces and lung tissues of mice deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF), with pathological findings resembling the histology seen in the human disease pulmonary alveolar proteinosis (PAP). Previous metabolic studies in GM-CSF-deficient [GM(-/-)] mice indicated that defects in surfactant clearance cause the surfactant accumulation in PAP. In the present study, GM(-/-) mice were treated daily or weekly with recombinant mouse GM-CSF by aerosol inhalation or intraperitoneal injection for 4-5 wk. Lung histology, alveolar macrophage differentiation, and surfactant protein B immunostaining returned toward normal levels in the GM-CSF aerosol-treated mice. Alveolar and lung tissue saturated phosphatidylcholine and surfactant protein B concentrations were significantly decreased after treatment with aerosolized GM-CSF. Cessation of aerosolized GM-CSF for 5 wk resulted in increased saturated phosphatidylcholine pool sizes that returned to pretreatment levels. In contrast, PAP did not improve in GM(-/-) mice treated daily for 5 wk with larger doses of systemic GM-CSF. Aerosolized GM-CSF improved PAP in the GM(-/-) mice, demonstrating that surfactant homeostasis can be influenced by local administration of GM-CSF to the respiratory tract.

Sacral agenesis and neurogenic bladder: Long-term outcomes of bladder and kidney function

BACKGROUND Sacral agenesis (SA) is a rare congenital condition that refers to the absence of part or all of two or more lower sacral vertebral bodies. It can be associated with neurogenic bladder dysfunction that does not necessarily correlate with the level of spinal or skeletal defect. Patients with SA should undergo urodynamic studies (UDS) to guide lower urinary tract (LUT) management. OBJECTIVE This review aimed to update the present institutional experience since 1981 of this rare patient population with detailed, long-term follow-up of bladder and kidney function. STUDY DESIGN A single institution, retrospective, IRB-approved review was performed on patients born after January 1, 1981 with an isolated diagnosis of sacral agenesis without spina bifida, and followed with urologic involvement at Boston Childrens Hospital. Records were reviewed for demographics, radiologic imaging, UDS including cystometrogram (CMG) and electromyography (EMG), surgery, and blood chemistries. Comparisons were made between groups of patients based on age at diagnosis, with specific focus on renal function and stability of neurogenic bladder lesion. RESULTS Forty-three patients were identified: 23 female and 20 male. Thirty-seven children (86%) had a known age of diagnosis. Nineteen were diagnosed before 2 months old, including five who were diagnosed prenatally, 11 were diagnosed between 2 and 18 months, and seven were diagnosed after 18 months. All 43 had UDS, with 24 (55.8%) studied at the time of diagnosis (Summary Table). Twenty had serial full UDS, with 30% demonstrating neurourologic instability. None developed end-stage renal disease (ESRD) or required spinal cord detethering. DISCUSSION Many children with SA appeared to be diagnosed prenatally or early in life; SA was mostly identified during evaluation of associated anomalies. Though UDS aid in urologic management, testing was not routinely utilized at the time of diagnosis. CONCLUSIONS This review of long-term follow-up in SA patients showed stable LUT and renal function, with minimal risk of progression to ESRD.

Urinary Proteomics Yield Pathological Insights for Ureteropelvic Junction Obstruction

Prenatal hydronephrosis is a common condition that may spontaneously resolve after birth. However, this condition can result in renal damage and requires surgical correction in a number of cases. Preventing renal damage is paramount, but existing diagnostic technology is invasive, exposes infants to radiation, is costly, and is often indeterminate. A better understanding of the pathophysiology of renal obstruction as reflected in the urinary proteome may provide new insights into the disease that could potentially alter the clinical management of hydronephrosis. We performed a quantitative proteomics study of urine that was surgically obtained from eight clinically significant, unilaterally obstructed infants versus eight healthy controls, with the goal of identifying quantitatively varying proteins and the biological networks associated with them. Notably, urine was obtained from both the obstructed kidney and the bladder. Over 1100 proteins were identified, and a total of 76 quantitatively varying proteins were identified. Proteins involved in oxidative stress, inflammation, and renal disease pathways showed the most significant abundance differences. This study gives a deeper understanding of the critical proteomic changes associated with renal obstruction and represents the deepest proteomic profile of renal obstruction to date.

The Surgical Management of Male Epispadias in the New Millennium

Male epispadias is a rare and challenging urologic condition. As part of the epispadias-exstrophy complex of genitourinary anomalies, it covers a broad spectrum with the mildest forms being the rarest. The anatomic classification into glanular, penile, and penopubic is based on the location of the urethral meatus. However, this classification fails to include some of the suprapubic malformations that may be present such as pubic diastasis, bladder neck abnormalities, and vesicoureteral reflux. Careful preoperative evaluation should allow the identification of these anomalies and will help achieve the goals of surgical reconstruction. These goals include cosmetic and functional reconstruction of the penis and urethra as well as, when needed, creation of a continence mechanism that will allow for normal bladder function, storage, and evacuation of urine. This review will focus on: 1) the preoperative evaluation and management of male patients with epispadias and 2) surgical management based on the anatomic classification.

V7-03 ROBOTIC PARTIAL NEPHRECTOMY WITH SELECTIVE CLAMPING FOR RENAL MASS IN <15KG PEDIATRIC PATIENT: TECHNIQUES ADAPTED FROM ADULT UROLOGY

INTRODUCTION AND OBJECTIVES: Radical dissection of the urogenital fibers and the thickened smooth and striated muscle fibers connecting the posterior urethra and bladder plate to the diastatic pubic rami is crucial for adequate placement of the posterior vesicourethral unit deep within the pelvis during classic bladder exstrophy (CBE) and cloacal exstrophy (CE) closure, as well as ensuring successful outcomes. Intraoperative magnetic resonance imaging (MRI) guided navigation of the pelvic floor offers a novel technique for identification of the urogenital diaphragm fibers and the thickened muscular attachments between the posterior urethra, bladder plate and pubic rami during CBE closure. METHODS: Institutional review board and Food and Drug Administration approval was obtained for use of Brainlab (Munich, Germany) intraoperative MRI-guided navigation of the pelvic floor anatomy during closure of CBE at the authors’ institution. Pre-operative pelvic MRI was obtained one day prior to exstrophy closure in patients necessitating pelvic osteotomies. Intraoperative registration was performed after pre-operative planning with a pediatric radiologist utilizing five anatomic landmarks immediately prior to initiation of surgery. Accuracy of identification of pelvic anatomy was assessed by three pediatric urologic surgeons and one pediatric radiologist. RESULTS: 32 patients with CBE and 2 patients with CE closed at the authors’ institution have successfully utilized Brainlab technology to navigate and guide the dissection of the pelvic floor intraoperatively. All patients had 100% accuracy in correlation of gross anatomic landmarks with MRI identified landmarks intraoperatively, and all have had successful closure without any complication. CONCLUSIONS: Brainlab intraoperative MRI-guided pelvic floor navigation and dissection is an effective way to accurately identify pelvic anatomy during CBE and CE closure. Future assessment of realtime changes in pelvic floor anatomy comparing pre-closure to postclosure MRI will allow quantification of pelvic floor anatomy in these patients and may allow for intra-institutional telementoring in this most important first step of exstrophy reconstruction.

Anatomic findings associated with epispadias in boys: Implications for surgical management and urinary continence

INTRODUCTION Pre-operative physical examination of male epispadias allows for classification of epispadias level as glanular (GE), penile (PE) or penopubic (PPE), and for delineation of anatomic anomalies. The incidence of associated extragenital abnormalities, such as vesicoureteral reflux (VUR), bladder neck (BN) abnormality and abnormal pubic diastasis (PD), and their impact on urinary continence has not yet been systematically studied. OBJECTIVE The goal of this study was to evaluate whether the more proximal level of epispadias correlated with associated extragenital anatomic anomalies seen on initial imaging or endoscopic evaluation, and whether these pre-operative findings contributed to subsequent surgical management and impacted on achieving urinary continence. It was hypothesized that the more severe forms of epispadias may be associated with a higher frequency of associated anomalies. STUDY DESIGN The study was an IRB-approved, retrospective case study of all male patients treated initially for isolated epispadias at the current institution between 1994 and 2011. Data collection was achieved by chart and radiology review evaluating PD, BN appearance, presence of VUR, surgical treatment, and urinary continence. RESULTS A total of 26 patients were identified and divided into three groups based on appearance at physical examination: four glanular (GE), eight penile (PE), and 14 penopubic (PPE); 17 patients had an abnormal BN. Reflux was noted in nine of 20 patients who had a voiding cystourethrogram (VCUG), two of which had an episode of pyelonephritis. Of the 22 patients past the age of toilet training, 17 were continent (64% (9/14) penopubic, 63% (5/8) penile, and 75% (3/4) glanular). DISCUSSION Anatomic classification for male epispadias did not provide sufficient information regarding extragenital findings. This study provided new information regarding PD, BN appearance, presence of reflux, and ultimate urinary continence. Pubic diastasis and BN abnormalities were more frequently seen in more severe forms of epispadias, whereas VUR seemed more prevalent in less severe forms. A template for pre-operative evaluation was outlined. Limitations of the study were its retrospective design and relatively small cohort of patients, which reflected the rarity of the condition. CONCLUSION Based on the information generated, additional anatomic information was generated regarding boys with epispadias. This information will help guide the evaluation and the management of these patients in the future.

V7-11 PEDIATRIC ROBOT-ASSISTED LAPAROSCOPIC EXCISION OF ECTOPIC DISTAL URETERAL STUMP

RESULTS: Surgery was uneventful. Identification of the distal ureter was somewhat challenging, but landmarks, such as the iliac bifurcation allowed for localization. The placement of both robotic ports along the midclavicular line provided maximum access to the distal and proximal segments of the ureter, aiding in our dissection. The ureter was transected proximally and distally to the stenotic segment. The retrocaval portion of the ureter was left in place though in discontinuity. The anastomosis was performed using a 5-0 PDS continuous suture. Operative time was 159 minutes, and EBL was 20mL. A 6x28 JJ internal ureteral stent was left in place for one month. The patient awaits further follow-up. CONCLUSIONS: A robotic-assisted approach to repair of a retrocaval ureter is a safe alternative to the conventional open approach. Identification of the distal ureter can be challenging, but the use of landmarks, such as the iliac bifurcation, as well as selective port placement can assist the dissection.