Jaspreet S. Sandhu

Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy

Introduction: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic. Aim: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2. Methods: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family). Results: We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2. Conclusion: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.

Contemporary Management of Postprostatectomy Incontinence

CONTEXT In recent years, despite improvement in the surgical technique, the prevalence of postprostatectomy incontinence has increased due to a rise in the number of radical prostatectomies performed annually. OBJECTIVE The aim of this review is to evaluate contemporary noninvasive and invasive treatment options for postprostatectomy incontinence. EVIDENCE ACQUISITION In August 2010, a review of the literature was performed using the Medline database. EVIDENCE SYNTHESIS All articles concerning noninvasive and invasive treatment for postprostatectomy incontinence were included. CONCLUSIONS No randomised controlled trials exist to compare currently used noninvasive and invasive treatments for postprostatectomy incontinence. Pelvic floor muscle training is recommended for the initial treatment of stress urinary incontinence (SUI). Additionally, antimuscarinic therapy should be applied for urgency or urge incontinence. For decades, the artificial urinary sphincter was the reference standard for persistent SUI. Nowadays, male slings are an alternative for men with mild to moderate postprostatectomy SUI.

Contemporary Open and Robotic Radical Prostatectomy Practice Patterns Among Urologists in the United States

PURPOSE We describe current trends in robotic and open radical prostatectomy in the United States after examining case logs for American Board of Urology certification. MATERIALS AND METHODS American urologists submit case logs for initial board certification and recertification. We analyzed logs from 2004 to 2010 for trends and used logistic regression to assess the impact of urologist age on robotic radical prostatectomy use. RESULTS A total of 4,709 urologists submitted case logs for certification between 2004 and 2010. Of these logs 3,374 included 1 or more radical prostatectomy cases. Of the urologists 2,413 (72%) reported performing open radical prostatectomy only while 961 (28%) reported 1 or more robotic radical prostatectomies and 308 (9%) reported robotic radical prostatectomy only. During this 7-year period we observed a large increase in the number of urologists who performed robotic radical prostatectomy and a smaller corresponding decrease in those who performed open radical prostatectomy. Only 8% of patients were treated with robotic radical prostatectomy by urologists who were certified in 2004 while 67% underwent that procedure in 2010. Median age of urologists who exclusively performed open radical prostatectomy was 43 years (IQR 38-51) vs 41 (IQR 35-46) for those who performed only robotic radical prostatectomy. CONCLUSIONS While the rate was not as high as the greater than 85% industry estimate, 67% of radical prostatectomies were done robotically among urologists who underwent board certification or recertification in 2010. Total radical prostatectomy volume almost doubled during the study period. These data provide nonindustry based estimates of current radical prostatectomy practice patterns and further our understanding of the evolving surgical treatment of prostate cancer.

Recovery of Urinary Continence after Radical Prostatectomy: Association with Urethral Length and Urethral Fibrosis Measured by Preoperative and Postoperative Endorectal Magnetic Resonance Imaging

BACKGROUND Limited data on endorectal magnetic resonance imaging (MRI) features and urinary continence after radical prostatectomy (RP) are available. OBJECTIVE To assess whether recovery of urinary continence after RP is associated with endorectal MRI findings regarding preoperative and postoperative membranous urethral length (MUL), percent change in MUL, and postoperative urethral and periurethral fibrosis. DESIGN, SETTING, AND PARTICIPANTS Sixty-four patients who received an MRI scan before and after RP for localized prostate cancer were evaluated in a retrospective study at a single institution. INTERVENTION All patients underwent RP. MEASUREMENTS The postoperative scan was performed to detect local recurrence in patients with rising levels of prostate-specific antigen. Urinary continence was graded on a five-point scale. MUL was measured on T2-weighted images. Urethral and periurethral fibrosis was graded from 0 to III based on axial T2-weighted images. Univariate Cox proportional hazards regression was performed to assess variables associated with continence. RESULTS AND LIMITATIONS Forty-eight patients regained continence following surgery. The median follow-up for patient who were incontinent at their last assessment was 7 mo. The median interval from RP to postoperative endorectal MRI was 10 mo. A longer preoperative or postoperative MUL was associated with superior continence (both p<0.01). The MUL loss ratio was significantly associated with postoperative continence (p=0.02). Patients with a high grade of postoperative periurethral fibrosis tended to have worse postoperative continence; nevertheless a statistical correlation was not reached (hazard ratio: 0.64, p=0.16). This is a retrospective study. CONCLUSIONS Preoperative and postoperative MUL and the MUL loss ratio are related to the recovery time and level of urinary continence after RP. Therefore, preservation of urethral length during surgery is recommended. Periurethral fibrosis might impede the recovery of continence after RP by altering the elasticity of the external sphincter.

Temporal Trends in Adoption of and Indications for the Artificial Urinary Sphincter

PURPOSE The introduction of the artificial urinary sphincter represented a significant advance in treating urinary incontinence. We examined temporal trends in artificial urinary sphincter use, focusing on adoption of the device with time, individual surgeon volume, indications for placement and differences in application by gender. MATERIALS AND METHODS Data on artificial urinary sphincter related operations performed in the United States from 1975 and thereafter were provided by the manufacturer. Surgical and demographic data on each patient were recorded and analyzed on an annual basis at 5-year intervals to determine the number of procedures performed as well as individual surgeon volume. Indications for implantation or revision were also studied and recorded in 5-year increments. RESULTS Artificial urinary sphincter use increased dramatically from 11 cases in 1975 to 3,762 in 2005. Most increased volume was due to an increase in device use in men with little growth in use in women. More than 90% of surgeons who participated in artificial urinary sphincter surgery performed 5 or fewer related cases per year (median 1 to 2) in most years. The annual proportion of revision surgeries stabilized after an initial increase. The most prevalent indication for initial implantation in men from 1985 and thereafter was incontinence after radical prostatectomy. In women neurogenic disease was consistently the most common indication for placement. CONCLUSIONS Artificial urinary sphincter use has increased dramatically in the United States since 1975 and it now appears to be stable. Placement is primarily performed in men with incontinence after radical prostatectomy. Only a small minority of surgeons perform a high volume of artificial urinary sphincter cases.

Trends in the use of incontinence procedures after radical prostatectomy: a population based analysis.

PURPOSE Urinary incontinence is a frequent complication of radical prostatectomy with a detrimental impact on quality of life. We identified predictors and trends in the use of procedures for post-prostatectomy incontinence. MATERIALS AND METHODS Using SEER (Surveillance, Epidemiology and End Results) cancer registry data linked with Medicare claims, we identified men 66 years old or older who were treated with radical prostatectomy in 2000 to 2007. The primary outcome was performance of an incontinence procedure. Demographic and clinical predictors of incontinence surgery were evaluated by multivariable regression analysis. RESULTS Of 16,348 men treated with radical prostatectomy 1,057 (6%) had undergone at least 1 incontinence procedure by a median of 20 months after the procedure, including 61% who underwent the first incontinence procedure within 2 years of prostatectomy. Older age and residence in the South were associated with greater probability of an incontinence procedure. Black men and those living in nonmetropolitan areas were less likely than their peers to undergo an incontinence procedure. Of men treated with any incontinence procedure 15% underwent more than 1 type. Of those treated with bulking agents 39% also received a urethral sling or artificial urinary sphincter and 13% who received a sling also had an artificial urinary sphincter. In 34% of the men who underwent any incontinence surgery artificial urinary sphincter placement was the only procedure performed. CONCLUSIONS In this population based cohort of older men with prostate cancer only 6% underwent an incontinence procedure after prostatectomy. This low rate may reflect the underuse of potentially beneficial procedures.

Recovery of Urinary Function After Radical Prostatectomy: Predictors of Urinary Function on Preoperative Prostate Magnetic Resonance Imaging

PURPOSE We determined whether pelvic soft tissue and bony dimensions on endorectal magnetic resonance imaging influence the recovery of continence after radical prostatectomy, and whether adding significant magnetic resonance imaging variables to a statistical model improves the prediction of continence recovery. MATERIALS AND METHODS Between 2001 and 2004, 967 men undergoing radical prostatectomy underwent preoperative magnetic resonance imaging. Soft tissue and bony dimensions were retrospectively measured by 2 raters blinded to clinical and pathological data. Patients who received neoadjuvant therapy, who were preoperatively incontinent or had missing followup for continence were excluded from study, leaving 600 patients eligible for analysis. No pad use defined continent. Logistic regression was used to identify variables associated with continence recovery at 6 and 12 months. We evaluated whether the predictive accuracy of a base model was improved by adding independently significant magnetic resonance imaging variables. RESULTS Urethral length and urethral volume were significantly associated with the recovery of continence at 6 and 12 months. Larger inner and outer levator distances were significantly associated with a decreased probability of regaining continence at 6 or 12 months, but they did not reach statistical significance for other points. Addition of these 4 magnetic resonance imaging variables to a base model including age, clinical stage, prostate specific antigen and comorbidities marginally improved the discrimination (12-month AUC improved from 0.587 to 0.634). CONCLUSIONS Membranous urethral length, urethral volume, and an anatomically close relation between the levator muscle and membranous urethra on preoperative magnetic resonance imaging are independent predictors of continence recovery after radical prostatectomy. The addition of magnetic resonance imaging variables to a base model improved the predictive accuracy for continence recovery, but the predictive accuracy remains low.

Prostate Size is Associated With Surgical Difficulty but Not Functional Outcome at 1 Year After Radical Prostatectomy

PURPOSE We assessed the impact of prostate size on operative difficulty as measured by estimated blood loss, operating room time and positive surgical margins. In addition, we assessed the impact on biochemical recurrence and the functional outcomes of potency and continence at 1 year after radical prostatectomy as well as postoperative bladder neck contracture. MATERIALS AND METHODS From 1998 to 2007, 3,067 men underwent radical prostatectomy by 1 of 5 dedicated prostate surgeons with no neoadjuvant or adjuvant therapy. Pathological specimen weight was used as a measure of prostate size. Cox proportional hazards and logistic regression analysis was used to study the association between specimen weight, and biochemical recurrence and surgical margin status, respectively, controlling for adverse pathological features. Continence and potency were analyzed controlling for age, nerve sparing status and surgical approach. RESULTS With increasing prostate size there was increased estimated blood loss (p = 0.013) and operative time (p = 0.004), and a decrease in positive surgical margins (84 of 632 [14%] for 40 gm or less, 99 of 862 [12%] for 41 to 50 gm, 78 of 842 [10%] for 51 to 65 gm, 68 of 731 [10%] for more than 65 gm, p <0.001). Biochemical recurrence was observed in 186 of 2,882 patients followed postoperatively and was not significantly associated with specimen weight (p = 0.3). Complete continence was observed in 1,165 of 1,422 patients (82%) and potency in 425 of 827 (51%) at 1 year. Specimen weight was not significantly associated with potency (p = 0.8), continence (p = 0.08) or bladder neck contracture (p = 0.22). CONCLUSIONS Prostate size does not appear to affect biochemical recurrence or 1-year functional results. However, estimated blood loss and operative time increased with larger prostate size, and positive surgical margins are more often observed in smaller glands.

The Surgical Learning Curve for Artificial Urinary Sphincter Procedures Compared to Typical Surgeon Experience

BACKGROUND The artificial urinary sphincter (AUS) is a well-established treatment for male stress urinary incontinence. OBJECTIVE We aimed to characterize the surgical learning curve for reoperation rates after AUS implantation. DESIGN, SETTING, AND PARTICIPANTS The study cohort consisted of 65 602 adult males who received an AUS between 1988 and 2008, constituting close to 90% of all operations conducted during that time. Data on reoperations were obtained from the manufacturer, which requires documentation for warranty coverage. MEASUREMENTS Surgeon experience was calculated as the number of original AUS implants performed prior to the index patients surgery. Multivariable logistic regression models were used to examine the association between experience and reoperative rates, adjusted for case mix. RESULTS AND LIMITATIONS There was a slow but steady decrease in reoperative rates with increasing surgeon experience (p=0.020), showing no plateau through 200 procedures. The risk of reoperation for a surgeon with five prior cases was 24.0%, which decreased to 18.1% for a surgeon with 100 prior implants (absolute risk difference [ARD]: 5.9%; 95% confidence interval [CI], 1.3-10.1%) and to 13.2% for a surgeon with 200 prior implants (ARD: 10.7%; 95% CI, 2.6-16.6%). Two-thirds of contemporary patients (having AUS procedure between years 2000 and 2008) saw a surgeon who had done ≤25 prior AUS implants; only 9% saw a surgeon with ≥100 prior procedures. CONCLUSIONS The learning curve for AUS surgery appears to be very long and without an obvious plateau. This is in contrast to typical surgeon experience, suggesting a considerable burden of avoidable reoperations. Efforts to flatten the learning are urgently needed.

Factors Predicting Early Return of Continence After Radical Prostatectomy

Success of radical prostatectomy is measured by control of cancer and return of urinary and sexual function. Urinary incontinence is generally considered the greatest impairment in immediate postoperative urinary function. Multiple factors are associated with earlier return of urinary continence after radical prostatectomy. These factors can be divided into those known prior to surgery, and therefore possibly not modifiable, and factors that can be controlled during surgery or surgical planning. In addition, various postoperative maneuvers can help hasten urinary continence. This article examines the effect of known factors related to early return of urinary continence after radical prostatectomy.