Mesenchymal stem cell therapy inhibited inflammatory and profibrotic pathways induced by partial bladder outlet obstruction and prevented high-pressure urine storage.

BACKGROUND: Partial bladder outlet obstruction (pBOO) is characterized by an initial inflammatory response that progresses to smooth muscle hypertrophy and fibrosis. Current treatment modalities carry high risk of morbidity. Mesenchymal stem cells (MSCs) are undifferentiated adult cells with reparative, immunomodulatory, and anti-inflammatory capacities. The ability of MSCs to inhibit inflammatory and profibrotic pathways in bladder cells has been recently reported. OBJECTIVES: This study aimed to investigate the therapeutic effects of MSCs on pBOO-induced inflammatory, profibrotic signaling pathways and end-organ physiology. MATERIALS AND METHODS: Twenty Sprague Dawley rats were randomly assigned to 5 groups: unobstructed controls, pBOO for 2 and 4 weeks, pBOO+MSCs for 2 and 4 weeks. Partial bladder outlet obstruction was surgically induced followed by intravenous injection of MSCs. Endpoint urodynamics was performed, and bladder tissue harvested for analysis. Reverse transcription real time polymerase chain reaction (RT-PCR) and immunohistochemistry were performed to study gene and protein expression of major inflammatory and profibrotic markers. RESULTS: Partial bladder outlet obstruction resulted in an upregulation of transforming growth factor beta (TGFß1), mothers against decapentaplegic homolog 2/3 (SMAD2/3), hypoxia inducible factor 1 alpha (HIF1α), hypoxia inducible factor 3 alpha (HIF3α), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNFα), mechanistic target of rapamycin (mTOR), p70 ribosomal S6 protein kinase (p70 S6K), collagen 1 (COL1), and collagen 3 (COL3) expression in a time-dependent manner. This was coupled with a downregulation of interleukin (IL)-10 expression. Increase of bladder fibrosis was directly related to the duration of pBOO and associated with high urine storage pressure. Injected MSCs were identified in the bladder 4 weeks after therapy. The immunomodulatory effect of MSCs(defined by reduced TNFα and increased IL-10 and VEGF) was most predominant 2 weeks after therapy. Significant downregulation of profibrotic genes occurred 4 weeks after therapy. End filling pressure, hypertrophy, and fibrosis were significantly reduced after MSC therapy (P < 0.05). DISCUSSION: Mesenchymal stem cell therapy led to a profound systematic improvement of the obstructed bladder. This included an initial anti-inflammatory response and a subsequent antifibrotic reaction. Essentially, both phases were associated with a reduction of urine storage pressure. The intravenously injected MSCs were tracked in the bladder. However, their presence in non-target organs such as the lungs, spleen, and liver was not tracked. CONCLUSIONS: Partial bladder outlet obstruction induced significant upregulation of hypoxic, inflammatory, and profibrotic markers. Mesenchymal stem cell therapy potently inhibited these pathways and improved bladder function.

Development of an objective score to quantify the pediatric cystometrogram.

PURPOSE: We developed a reliable tool for quantitative assessment of the pediatric cystometrogram. MATERIALS AND METHODS: Scores for expected capacity (EV), compliance (EV20), activity and sensation were developed according to established formulas for norms. Ordinal scores were derived by calculating observed over expected findings. Based on the derived percents scores of 1 to 5 were assigned. For EV--0 to 5 the formula used was EV = (age + 2) x 30 and for EV20--0 to 5 the formula used was EV20 = 17 x age + 55. Activity was determined as the volume of the first, total number and magnitude of involuntary contractions, each scored 0 to 5 and divided by 3. Sensation was scored as 0 to 3 according to volume at first sensation. A total of 87 blinded cystometrograms in 49 patients were independently scored twice by 3 pediatric urologists. The resultant 522 total and 2,088 component scores were assessed for reliability. RESULTS: Intrarater reliability was strong with 80% of total scores (208 of 261) within +/- 1 point from initial to subsequent retest. Reliability component scores were stronger with 94% (983 of 1,044) within +/- 1 point from test to retest. Spearman's rank correlations for total score was 0.82 to 0.98, indicating a strong relationship between test and retest. Interrater reliability of components was strong with 89% of scores (1,851 of 2,088) between urologists within +/- 1 point. Correlation coefficients for total scores were 0.80 to 0.96, indicating a high degree of consistency between urologist assessments (p <0.05). CONCLUSIONS: This score appears to reliably quantify the pediatric cystometrogram. Its application may be useful for the objective assessment of detrusor behavior before and after intervention. Further applications should allow refinement of this tool.

Use of the mobilized sinus with total urogenital mobilization.

PURPOSE: The surgical treatment of urogenital sinus anomalies has undergone significant advances in recent years. Total urogenital mobilization, which mobilizes the urogenital sinus, vagina and urethra en bloc toward the perineum, represents one of these advances. MATERIALS AND METHODS: We have improved our results with total urogenital mobilization by incorporating the mobilized urogenital sinus tissue into the repair rather than discarding it, as described originally. We have found this a readily available, easily manipulated and well vascularized flap that is a significant aid to reconstruction. RESULTS: We present our 3 favored means of using the mobilized sinus tissue to create a mucosa lined vestibule, a posterior vaginal wall flap and an anterior vaginal wall flap. CONCLUSIONS: We believe that our techniques result in a further advancement in the cosmetic and surgical outcomes in these patients, and are beneficial in the reconstructive surgery armamentarium.

Total continence reconstruction: a comparison to staged reconstruction of neuropathic bowel and bladder.

PURPOSE: Surgical treatment for neuropathic bowel and bladder has become an essential tool in maximizing the quality of life in patients with myelomeningocele. We present our results comparing results in patients who underwent total continence reconstruction of the urinary and gastrointestinal tracts to patients who underwent a separate or single operation. MATERIALS AND METHODS: We performed a retrospective chart review of all patients with myelomeningocele at our institution who underwent reconstruction with a cutaneous catheterizable urinary channel or Malone antegrade continence enema. We compared outcomes with regard to surgical revisions of the channel between patients who underwent the construction of each simultaneously, that is total continence reconstruction, to outcomes in those with a single channel or who underwent reconstruction at 2 or more operations. RESULTS: Most of our patients underwent genitourinary and gastrointestinal reconstruction, and few desired surgical intervention for only a single system. We were unable to find any differences in the continence rate or stomal complications. However, patients who underwent staged reconstruction usually had significant secondary reasons for repeat surgery. CONCLUSIONS: Surgical success for urinary and fecal continence can be safely and effectively achieved through single or multiple procedures. However, because of shared pathophysiology, we believe that most patients benefit from intervention in the gastrointestinal and the genitourinary tract. Therefore, a major advantage of total continence reconstruction is avoidance of the morbidity of a second major surgical procedure.

What is the need for additional bladder surgery after bladder augmentation in childhood?

PURPOSE: Bladder augmentation has revolutionized the care of children with a neuropathic bladder but it remains a major surgical procedure. However, the need for subsequent bladder surgery has not been well defined in a large series with long-term followup. MATERIALS AND METHODS: We retrospectively reviewed the records of the first 500 bladder augmentations performed from 1978 to 2003 at our institution. Charts were reviewed for complications requiring additional surgery, including malignancy, bladder perforation, repeat augmentation, bowel obstruction and bladder calculi. Mean and median followup was 13.3 years. RESULTS: Complications occurred in 169 patients (34%) resulting in a total of 254 surgeries. The cumulative risk of further surgery at the bladder level was 0.04 operations per patient per year of augmentation. Three patients (0.6%) had transitional cell carcinoma, of whom all presented with metastatic disease and died. Bladder perforation occurred in 43 patients (8.6%) with a total of 53 events. Of the patients 16 (3.2%) required laparotomy for bowel obstruction and 47 (9.4%) required repeat augmentation. Bladder stones were treated in 75 patients (15%), who required a total of 125 surgeries. CONCLUSIONS: Bladder augmentation provides immeasurable improvements in quality of life but it requires lifelong dedication from the patient, family and health care providers. While the requirements for additional surgery are not trivial, 66% of our patients have not required any further surgery in the augmented bladder.

Treatment of the occult tethered spinal cord for neuropathic bladder: results of sectioning the filum terminale.

PURPOSE: Occult tethered cord syndrome applies to patients with signs and symptoms consistent with a caudal spinal cord malformation despite normal neuroimaging. Although several reports of successful surgical treatment exist, controversy remains with respect to patient selection and efficacy. We present a large series with excellent clinical followup, neuroimaging and urodynamic characterization. MATERIALS AND METHODS: We present our experience with 36 patients at a single institution with preoperative clinical findings, neuroimaging and urodynamics available. Postoperative outcomes were assessed clinically and with urodynamics. We determined predictive parameters to improve patient selection. RESULTS: Approximately 0.04% of pediatric urology clinic visits resulted in neurosurgical referral for the potential of an occult tethered cord. They occurred after failure of a mean of 2 years of aggressive medical management. Daytime urinary incontinence was present in 83% of patients and 47% had encopresis. Preoperative urodynamics were markedly abnormal in all patients with mean bladder capacity 55% of expected capacity. Clinical improvement in urinary symptoms was seen in 72% of patients with resolution of incontinence in 42%. Bowel symptoms improved in 88% of cases, including resolution of encopresis in 53% within 3 months of surgery. Urodynamic improvements were demonstrated in 57% of cases. We were unable to determine preoperative factors that were more likely associated with surgical success. CONCLUSIONS: In a highly select population with severe urinary and fecal dysfunction sectioning a normal-appearing filum terminale can result in significant improvement. We were unable to identify factors that may increase the chance of surgical success.

Spontaneous bladder perforations: a report of 500 augmentations in children and analysis of risk.

PURPOSE: The spontaneous perforation of an augmented bladder is an uncommon but serious complication. To our knowledge our institution has the largest reported series of bladder augmentations. We examined our data to determine the incidence of spontaneous bladder perforation and to delineate associated risk factors. MATERIALS AND METHODS: We performed a retrospective chart review of 500 bladder augmentation procedures performed during the preceding 25 years with a minimum followup of 2 years. RESULTS: Spontaneous perforations occurred in 43 patients (8.6%), for a total of 54 events. The calculated risk was 0.0066 perforations per augmentation-year at risk. Approximately a third of the cases had perforated within 2 years of surgery, a third between 2 and 6 years postoperatively, and a third at more than 6 years after augmentation. Patients who underwent augmentation between 1997 and 2003 had a higher rate of perforation within 2 years of surgery than those operated on between 1978 and 1987. Increased risk of perforation was observed with the use of sigmoid colon and bladder neck surgery. A decreased risk was associated with the presence of a continent catheterizable channel. CONCLUSIONS: We believe that this large and comprehensive series gives valuable insight into this serious complication. The delineation of these potential risk factors serves as a guide for further discussion and investigation.

Partial urogenital mobilization: a limited proximal dissection.

INTRODUCTION: The treatment of urogenital sinus malformations is complex and controversial. Despite numerous and significant contemporary surgical advances, the dissection of the urogenital sinus remains technically challenging. METHODS: Based on total urogenital mobilization, we describe a technique whereby this dissection is limited to the pubourethral ligament. Our short-term results with partial urogenital mobilization (PUM) performed on 15 patients are retrospectively reviewed. RESULTS: There were no intraoperative complications and the short-term cosmetic results are excellent. No patients have developed voiding dysfunction or urinary tract complications. CONCLUSIONS: While total urogenital mobilization is a very effective procedure, we believe that the PUM approach limits potential morbidity in the reconstruction of these complex problems.

Mitrofanoff channel survival after pedicle ligation.

In patients who have undergone complex genitourinary reconstruction, additional abdominal surgery is often required. We report 2 cases in which the blood supply to an existing Mitrofanoff channel was divided. In both cases, the conduits appeared to remain well perfused, presumably based on collateral blood supply. Both conduits remained healthy and functioning at more than 1 year of follow-up.

Bladder perforation during laparoscopic donor nephrectomy.

We present two cases of bladder perforation during laparoscopic donor nephrectomy at our institution. Neither of the surgeries was otherwise complicated, and the diagnoses were made post-operatively. The kidneys were extracted through a Pfannenstiel incision and used blunt dissection to penetrate the peritoneum. Both patients had previous tubal ligations, adhesions from which may have increased the chance of injury. We believe that this is a previously unreported complication that merits attention. Care should be taken with the peritoneal incision and dissection as the bladder may be susceptible to injury.

MCDK not excluded by virtue of function on renal scan.

INTRODUCTION: The conservative management of multicystic dysplastic kidneys (MCDK) has been very successful, largely due to advances in diagnostic imaging. Classically, MCDK is described as a non-functioning cystic renal mass. However, we noticed that the increasing sensitivity of renal scans is able to demonstrate function in MCDK that previously would not have been detected. METHODS: We describe eight cases of MCDK with elements of function on renal scan, and their follow up. RESULTS AND CONCLUSIONS: One half (4/8) of these children underwent nephrectomy, and histology was consistent with MCDK. The remaining 4/8 were successfully followed to radiographic involution, without any complications. Therefore, we believe that minimal function on nuclear scintigraphy does not preclude the diagnosis of MCDK, and is yet another adjustment in our understanding of this entity.