Renal IL-18 production is macrophage independent during obstructive injury.

BACKGROUND: Interleukin 18 (IL-18) is a pro-inflammatory cytokine that mediates fibrotic renal injury during obstruction. Macrophages are a well-known source of IL-18; however, renal tubular epithelial cells are also a potential source of this cytokine. We hypothesized that IL-18 is predominantly a renal tubular cell product and is produced during renal obstruction independent of macrophage infiltration. METHODS: To study this, male C57BL6 mice were subjected to unilateral ureteral obstruction (UUO) vs. sham operation in the presence or absence of macrophage depletion (liposomal clodronate (1 ml/100 g body weight i.v.)). The animals were sacrificed 1 week after surgery and renal cortical tissue harvested. Tissue levels of active IL-18 (ELISA), IL-18 receptor mRNA expression (real time PCR), and active caspase-1 expression (western blot) were measured. The cellular localization of IL-18 and IL-18R was assessed using dual labeling immunofluorescent staining (IFS). RESULTS: Immunohistochemical staining of renal tissue sections confirmed macrophage depletion by liposomal clodronate. IL-18 production, IL-18R expression, and active caspase 1 expression were elevated in response to renal obstruction and did not decline to a significant degree in the presence of macrophage depletion. Obstruction-induced IL-18 and IL-18R production localized predominantly to tubular epithelial cells (TEC) during obstruction despite macrophage depletion. CONCLUSION: These results demonstrate that renal tubular epithelial cells are the primary source of IL-18 production during obstructive injury, and that tubular cell production of IL-18 occurs independent of macrophage infiltration.

Nephrogenic adenoma in the augmented bladder.

PURPOSE: Nephrogenic adenoma is an uncommon, benign urothelial lesion. Risk factors for nephrogenic adenoma include trauma, chronic inflammation, immunosuppression and radiation. We characterized nephrogenic adenoma in the pediatric augmented bladder. MATERIALS AND METHODS: We reviewed the records of patients diagnosed with nephrogenic adenoma from January 2000 to March 2010. Those with prior bladder augmentation were studied further. Data were retrospectively obtained on pathological characteristics, cystoscopic findings, recurrence patterns and presentation. RESULTS: Ten patients with ileal bladder augmentation and nephrogenic adenoma were identified. The underlying pathological condition was myelodysplasia in 7 patients, sacral agenesis in 2 and bladder exstrophy in 1. Concomitant procedures were a continent channel in 9 patients, ureteroneocystostomy in 5 and bladder neck reconstruction in 7. Mean time to the discovery of nephrogenic adenoma was 9.2 years. During that time a total of 221 surveillance cystoscopies were performed in patients with bladder augmentation. The diagnosis was made by surveillance cystoscopy in 7 cases, at surgery for bladder stone in 2 and by cystoscopy for urinary incontinence in 1. Nephrogenic adenoma was identified along the floor in 5 cases, near the channel entrance in 3 and adjacent to the enteric anastomosis in 2. Six patients returned for surveillance with recurrence identified in 2. The longest recurrence free interval was 27 months. CONCLUSIONS: Nephrogenic adenoma is not uncommon in the augmented bladder and it is often asymptomatic. The lesions tend to develop at sites that may be prone to chronic catheterization injury. Recurrent lesions are not unusual.

IL-18 mediates proapoptotic signaling in renal tubular cells through a Fas ligand-dependent mechanism.

Renal tubular cell apoptosis is a significant component of obstruction-induced renal injury, and it results in a progressive loss in renal parenchymal mass during renal obstruction. Although IL-18 is an important mediator of inflammatory renal disease and renal fibrosis, its role in obstruction-induced renal tubular cell apoptosis remains unclear. To study this, male C57BL6 wild-type mice and C57BL6 mice transgenic for human IL-18-binding protein (IL-18BP Tg) were subjected to renal obstruction vs. sham operation. The kidneys were harvested after 1 or 2 wk and analyzed for IL-18 production, apoptosis, caspase activity, and Fas/Fas Ligand (FasL) expression. HK-2 cells were similarly analyzed for apoptosis and proapoptotic signaling following 3 days of direct exposure to IL-18 vs. control media. Renal obstruction induced a significant increase in IL-18 production, renal tubular cell apoptosis, caspase activation, and FasL expression. IL-18 neutralization, on the other hand, significantly reduced obstruction-induced apoptosis, caspase-8 and caspase-3 activity, and FasL expression. In vitro experiments similarly demonstrate that IL-18 stimulation induces apoptosis, FasL expression, and increases active caspase-8 and caspase-3 expression in a dose-dependent fashion. siRNA knockdown of FasL gene expression, however, significantly reduced IL-18-induced apoptosis. This study reveals that IL-18 is a significant mediator of obstruction-induced tubular cell apoptosis, and it demonstrates that IL-18 stimulates proapoptotic signaling through a FasL-dependent mechanism.

Treatment of moderate to severe female stress urinary incontinence with the adjustable continence therapy (ACT) device after failed surgical repair.

INTRODUCTION: Treatment of recurrent stress incontinence after a failed surgical procedure is more complicated, and repeat surgeries have higher rates of complications and limited efficacy. We determined the technical feasibility, efficacy, adjustability, and safety of adjustable continence therapy device for treatment of moderate to severe recurrent urinary incontinence after failed surgical procedure. MATERIALS AND METHODS: Female patients with moderate to severe recurrent stress urinary incontinence who had at least one prior surgical procedure for incontinence were enrolled. All patients underwent percutaneous placement of adjustable continence therapy (ACT) device (Uromedica, Plymouth, Minnesota). Baseline and regular follow-up tests to determine subjective and objective improvement were performed. RESULTS: A total of 89 patients have undergone implantation with 1-3 years of follow-up. Data are available on 77 patients at 1 year. Of the patients, 47% were dry at 1 year and 92% improved after 1-year follow-up. Stamey score improved from 2.25 to 0.94 at 1 year (P < 0.001). IQOL questionnaire scores improved from 33.9 to 71.6 at 1 year (P < 0.001). UDI scores reduced from 60.7 to 33.3 (P < 0.001) at 1 year. IIQ scores reduced from 57.0 to 21.6 (P < 0.001) at 1 year. Diary incontinence episodes per day improved from 8.1 to 3.9 (P < 0.001) at 1 year. Diary pads used per day improved from 4.3 to 1.9 (P < 0.001). Explantation was required in 21.7% of patients. CONCLUSION: The ACT device is an effective, simple, safe, and minimally invasive treatment for moderate to severe recurrent female stress urinary incontinence after failed surgical treatment.

The adjustable continence therapy system for recurrent female stress urinary incontinence: 1-year results of the North America Clinical Study Group.

PURPOSE: We determined the efficacy, safety, adjustability and technical feasibility of the adjustable continence therapy device (Uromedica, Plymouth, Minnesota) for the treatment of recurrent female stress urinary incontinence. MATERIALS AND METHODS: Female patients with recurrent stress urinary incontinence were enrolled in the study and a defined set of exclusionary criteria were followed. Baseline and regular followup tests to determine eligibility, and to measure subjective and objective improvement were performed. A trocar was passed fluoroscopically and with digital vaginal guidance to the urethrovesical junction through small incisions between the labia majora and minora. The adjustable continence therapy device was delivered and the balloons were filled with isotonic contrast. The injection ports for balloon inflation were placed in a subcutaneous pocket in each labia majora. Device adjustments were performed percutaneously in the clinic postoperatively. An approved investigational device exemption Food and Drug Administration protocol was followed to record all adverse events. RESULTS: A total of 162 subjects underwent implantation with 1 year of data available on 140. Mean Stamey score improved by 1 grade or more in 76.4% (107 of 140) of subjects. Improvement in the mean incontinence quality of life questionnaire score was noted at 36.5 to 70.7 (p <0.001). Reductions in mean Urogenital Distress Inventory (60.3 to 33.4) and Incontinence Impact Questionnaire (54.4 to 23.4) scores also occurred (p <0.001). Mean provocative pad weight decreased from 49.6 to 11.2 gm (p <0.001). Of the patients 52% (67 of 130) were dry at 1 year (less than 2 gm on provocative pad weight testing) and 80% (102 of 126) were improved (greater than 50% reduction on provocative pad weight testing). Complications occurred in 24.4% (38 of 156) of patients. Explantation was required in 18.3% (28 of 153) of the patients during 1 year. In terms of the complications 96.0% were considered to be mild or moderate. CONCLUSIONS: The Uromedica adjustable continence therapy device is an effective, simple, safe and minimally invasive treatment for recurrent female stress urinary incontinence. It can be easily adjusted percutaneously to enhance efficacy and complications are usually easily manageable. Explantation does not preclude later repeat implantation.

IL-6 does not predict current urolithiasis in stone formers.

INTRODUCTION: Interleukin-6 (IL-6), an inflammatory marker, has previously been found to be elevated in the urine of patients with urolithiasis. Oxalate and other stone precursors have been shown to increase IL-6 production in proximal tubular epithelial cells in vitro. We examined whether urinary IL-6 could be used as a screening test to determine current urolithiasis in individuals who are known to form urinary stones. METHODS: Thirty-five adult patients with current urolithiasis demonstrated on imaging were enrolled in the study. Exclusion criteria included disease known to elevate IL-6. Each patient provided a pre-treatment urine specimen and one month after proven to be stone-free an additional urine specimen was obtained. The urinary IL-6/creatinine ratio was determined for both specimens and compared. RESULTS: Ten patients provided both specimens. The mean pre-operative urinary IL-6/creatinine ratio before the procedure was 1.63 pg/mL. The mean post procedure urinary IL-6/creatinine ratio after the patient was confirmed to be stone-free was 1.81 pg/mL. These were not significantly different (p=0.38). Preoperative urinary IL-6/creatinine ratio did not correlate to stone size (r=0.15) and no correlation was seen between time from treatment and stone free IL-6/creatinine ratio (r=0.48). CONCLUSION: Urinary IL-6 is not a good screening test for current urolithiasis in stone-forming individuals. It is elevated whether the stone is present or not.

Usefulness of urinalysis in following patients with distal ureterolithiasis.

PURPOSE: The determine the usefulness of urinalysis in monitoring patients with distal ureterolithiasis. MATERIALS AND METHODS: Patients with microhematuria who were found to have a distal ureteral stone and who were candidates for conservative management were enrolled in the study. Patients were typically seen in clinic at 1 to 2 weeks after initial diagnosis and reassessed. A urinalysis, including office dipstick and automated laboratory analysis using the IQ 200 IRIS analyzer, were performed. The absence or presence of microhematuria was determined and compared with results of repeated unenhanced helical CT of the abdomen and pelvis to determine the sensitivity, specificity, and positive and negative predictive values of urinalysis. RESULTS: Twenty-nine patients were enrolled in this prospective study. The mean age of the patients was 43.5 years. The sex distribution was predominantly male, with 72% men and 28% women. Ultimately, 18 patients are included in our analysis with the remainder either lost to follow-up or excluded because of protocol violation. Average distal stone size was 4.1 mm (range 2.0-6.5 mm). Stones were evenly distributed between the right and the left ureters, with 50% on either side. Mean time to follow-up was 18 days with a range of 2 to 63 days. The sensitivity of urinalysis was determined to be 40% (8%-72%) while the specificity was 63% (28%-98%). The predictive value of a positive test was 57% (19%-95%) and the predictive value of a negative test was 55 % (25%-85%). The confidence interval for each of these parameters is inclusive of the value of 50%, indicating that urinalysis is no better than randomness in predicting presence or absence of a stone by CT. CONCLUSIONS: The absence or presence of microhematuria does not accurately predict whether a distal ureteral stone has passed or is still present. In those patients who need or want to know whether a stone is still present, unless a stone is strained, we suggest repeated CT imaging.