Intrarenal modulation of NF-κB activity attenuates cardiac injury in a swine model of CKD: a renal-cardio axis.

Patients with chronic kidney disease (CKD) have a high cardiovascular mortality. CKD and heart failure (HF) coexist in up to 50% of patients, and both associate with inflammation. We aimed to define the cardiac phenotype of a novel swine model of CKD and test the hypothesis that inflammation of renal origin propels the development of precursors of HF in CKD. CKD was induced in 14 pigs, which were followed for 14 wk. Renal (multidetector computed tomography) and cardiac (echocardiography) hemodynamics were quantified before and 8 wk after single intrarenal administration of placebo or a biopolymer-fused peptide inhibitor of NF-κB that blocks NF-κB activity and decreases inflammatory activity (SynB1-ELP-p50i). Blood was collected to quantify cytokines (TNF-α, monocyte chemoattractant protein-1, and interleukins), markers of inflammation (C-reactive protein), and biomarkers of HF (atrial and brain natriuretic peptides). Pigs were then euthanized, and kidneys and hearts were studied ex vivo. Normal pigs were used as time-matched controls. Renal dysfunction in CKD was accompanied by cardiac hypertrophy and fibrosis, diastolic dysfunction, increased renal and cardiac expression of TNF-α, monocyte chemoattractant protein-1, and interleukins, canonical and noncanonical mediators of NF-κB signaling, circulating inflammatory factors, and biomarkers of HF. Notably, most of these changes were improved after intrarenal SynB1-SynB1-ELP-p50i, although cardiac inflammatory signaling remained unaltered. The translational traits of this model support its use as a platform to test novel technologies to protect the kidney and heart in CKD. A targeted inhibition of renal NF-κB signaling improves renal and cardiac function, suggesting an inflammatory renal-cardio axis underlying early HF pathophysiology in CKD.NEW & NOTEWORTHY Chronic kidney disease (CKD) is a progressive disorder with high cardiovascular morbidity and mortality. This work supports the role of inflammatory cytokines of renal origin in renal-cardio pathophysiology in CKD and that the heart may be a target. Furthermore, it supports the feasibility of a new strategy in a translational fashion, using targeted inhibition of renal NF-κB signaling to offset the development of cardiac injury in CKD.

A dose-escalating toxicology study of the candidate biologic ELP-VEGF.

Vascular Endothelial Growth Factor (VEGF), a key mediator of angiogenesis and vascular repair, is reduced in chronic ischemic renal diseases, leading to microvascular rarefaction and deterioration of renal function. We developed a chimeric fusion of human VEGF-A121 with the carrier protein Elastin-like Polypeptide (ELP-VEGF) to induce therapeutic angiogenesis via targeted renal VEGF therapy. We previously showed that ELP-VEGF improves renal vascular density, renal fibrosis, and renal function in swine models of chronic renal diseases. However, VEGF is a potent cytokine that induces angiogenesis and increases vascular permeability, which could cause undesired off-target effects or be deleterious in a patient with a solid tumor. Therefore, the current study aims to define the toxicological profile of ELP-VEGF and assess its risk for exacerbating tumor progression and vascularity using rodent models. A dose escalating toxicology assessment of ELP-VEGF was performed by administering a bolus intravenous injection at doses ranging from 0.1 to 200 mg/kg in Sprague Dawley (SD) rats. Blood pressure, body weight, and glomerular filtration rate (GFR) were quantified longitudinally, and terminal blood sampling and renal vascular density measurements were made 14 days after treatment. Additionally, the effects of a single administration of ELP-VEGF (0.1-10 mg/kg) on tumor growth rate, mass, and vascular density were examined in a mouse model of breast cancer. At doses up to 200 mg/kg, ELP-VEGF had no effect on body weight, caused no changes in plasma or urinary markers of renal injury, and did not induce renal fibrosis or other histopathological findings in SD rats. At the highest doses (100-200 mg/kg), ELP-VEGF caused an acute, transient hypotension (30 min), increased GFR, and reduced renal microvascular density 14 days after injection. In a mouse tumor model, ELP-VEGF did not affect tumor growth rate or tumor mass, but analysis of tumor vascular density by micro-computed tomography (µCT) revealed significant, dose dependent increases in tumor vascularity after ELP-VEGF administration. ELP-VEGF did not induce toxicity in the therapeutic dosing range, and doses one hundred times higher than the expected maximum therapeutic dose were needed to observe any adverse signs in rats. In breast tumor-bearing mice, ELP-VEGF therapy induced a dose-dependent increase in tumor vascularity, demanding caution for potential use in a patient suffering from kidney disease but with known or suspected malignancy.

Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease.

BACKGROUND: Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial growth factor (VEGF) conjugated to an elastin-like polypeptide (ELP) carrier protein with an N-terminal kidney-targeting peptide (KTP). We tested the hypothesis that KTP-ELP-VEGF therapy will effectively recover renal function with an improved targeting profile. Further, we aimed to elucidate potential mechanisms driving renal recovery. METHODS: Unilateral RVD was induced in 14 pigs. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified by multidetector CT imaging. Pigs then received a single intrarenal injection of KTP-ELP-VEGF or vehicle. CT quantification of renal hemodynamics was repeated 4 weeks later, and then pigs were euthanized. Ex vivo renal microvascular (MV) density and media-to-lumen ratio, macrophage infiltration, and fibrosis were quantified. In parallel, THP-1 human monocytes were differentiated into naïve macrophages (M0) or inflammatory macrophages (M1) and incubated with VEGF, KTP-ELP, KTP-ELP-VEGF, or control media. The mRNA expression of macrophage polarization and angiogenic markers was quantified (qPCR). RESULTS: Intrarenal KTP-ELP-VEGF improved RBF, GFR, and MV density and attenuated MV media-to-lumen ratio and renal fibrosis compared to placebo, accompanied by augmented renal M2 macrophages. In vitro, exposure to VEGF/KTP-ELP-VEGF shifted M0 macrophages to a proangiogenic M2 phenotype while M1s were nonresponsive to VEGF treatment. CONCLUSIONS: Our results support the efficacy of a new renal-specific biologic construct in recovering renal function and suggest that VEGF may directly influence macrophage phenotype as a possible mechanism to improve MV integrity and function in the stenotic kidney.

Molecular targeting of renal inflammation using drug delivery technology to inhibit NF-κB improves renal recovery in chronic kidney disease.

Inflammation is a major determinant for the progression of chronic kidney disease (CKD). NF-κB is a master transcription factor upregulated in CKD that promotes inflammation and regulates apoptosis and vascular remodeling. We aimed to modulate this pathway for CKD therapy in a swine model of CKD using a peptide inhibitor of the NF-κB p50 subunit (p50i) fused to a protein carrier [elastin-like polypeptide (ELP)] and equipped with a cell-penetrating peptide (SynB1). We hypothesized that intrarenal SynB1-ELP-p50i therapy would inhibit NF-κB-driven inflammation and induce renal recovery. CKD was induced in 14 pigs. After 6 wk, pigs received single intrarenal SynB1-ELP-p50i therapy (10 mg/kg) or placebo (n = 7 each). Renal hemodynamics were quantified in vivo using multidetector computed tomography before and 8 wk after treatment. Pigs were then euthanized. Ex vivo experiments were performed to quantify renal activation of NF-κB, expression of downstream mediators of NF-κB signaling, renal microvascular density, inflammation, and fibrosis. Fourteen weeks of CKD stimulated NF-κB signaling and downstream mediators (e.g., TNF-α, monocyte chemoattractant protein-1, and IL-6) accompanying loss of renal function, inflammation, fibrosis, and microvascular rarefaction versus controls. All of these were improved after SynB1-ELP-p50i therapy, accompanied by reduced circulating inflammatory cytokines as well, which were evident up to 8 wk after treatment. Current treatments for CKD are largely ineffective. Our study shows the feasibility of a new treatment to induce renal recovery by offsetting inflammation at a molecular level. It also supports the therapeutic potential of targeted inhibition of the NF-κB pathway using novel drug delivery technology in a translational model of CKD.

Macrophage polarization in chronic kidney disease: a balancing act between renal recovery and decline?

Macrophages are heterogenous cells of the innate immune system that can fluidly modulate their phenotype to respond to their local microenvironment. They are found throughout the renal compartments, where they contribute to homeostasis and function. However, renal injury activates molecular pathways that initially stimulate differentiation of macrophages into a proinflammatory M1 phenotype. Later in the course of healing, abundant apoptotic debris and anti-inflammatory cytokines induce the production of anti-inflammatory M2 macrophages, which contribute to tissue regeneration and repair. Thus, the dynamic balance of M1 and M2 populations may outline the burden of inflammation and process of tissue repair that define renal outcomes, which has been the impetus for therapeutic efforts targeting macrophages. This review will discuss the role of these phenotypes in the progression of chronic renal injury, potential pathogenic mechanisms, and the promise of macrophage-based therapeutic applications for chronic kidney disease.

Targeted VEGF (Vascular Endothelial Growth Factor) Therapy Induces Long-Term Renal Recovery in Chronic Kidney Disease via Macrophage Polarization.

Chronic kidney disease (CKD) universally associates with renal microvascular rarefaction and inflammation, but whether a link exists between these 2 processes is unclear. We designed a therapeutic construct of VEGF (vascular endothelial growth factor) fused to an ELP (elastin-like polypeptide) carrier and show that it improves renal function in experimental renovascular disease. We test the hypothesis that ELP-VEGF therapy will improve CKD, and that recovery will be driven by decreasing microvascular rarefaction partly via modulation of macrophage phenotype and inflammation. CKD was induced in 14 pigs, which were observed for 14 weeks. At 6 weeks, renal blood flow and filtration were quantified using multidetector computed tomography, and then pigs received single intrarenal ELP-VEGF or placebo (n=7 each). Renal function was quantified again 4 and 8 weeks later. Pigs were euthanized and renal microvascular density, angiogenic and inflammatory markers, fibrosis, macrophage infiltration, and phenotype were quantified. Loss of renal hemodynamics in CKD was progressively recovered by ELP-VEGF therapy, accompanied by improved renal microvascular density, fibrosis, and expression of inflammatory mediators. Although renal macrophage infiltration was similar in both CKD groups, ELP-VEGF therapy distinctly shifted their phenotype from proinflammatory M1 to VEGF-expressing M2. Our study unravels potential mechanisms and feasibility of a new strategy to offset progression of CKD using drug-delivery technologies. The results indicate that renal recovery after ELP-VEGF therapy was largely driven by modulation of renal macrophages toward VEGF-expressing M2 phenotype, restoring VEGF signaling and sustaining improvement of renal function and microvascular integrity in CKD.

Biopolymer-delivered vascular endothelial growth factor improves renal outcomes following revascularization.

Renal angioplasty and stenting (PTRAs) resolves renal artery stenosis, but inconsistently improves renal function, possibly due to persistent parenchymal damage. We developed a bioengineered fusion of a drug delivery vector (elastin-like polypeptide, ELP) with vascular endothelial growth factor (VEGF), and showed its therapeutic efficacy. We tested the hypothesis that combined ELP-VEGF therapy with PTRAs improves renal recovery more efficiently than PTRAs alone, by protecting the stenotic renal parenchyma. Unilateral renovascular disease (RVD) was induced by renal artery stenosis in 14 pigs. Six weeks later, stenotic kidney blood flow (RBF) and glomerular filtration rate (GFR) were quantified in vivo using multidetector CT. Blood and urine were collected during in vivo studies. All pigs underwent PTRAs and then were randomized into single intrarenal ELP-VEGF administration or placebo (n = 7 each) groups. Pigs were observed for four additional weeks, in vivo CT studies were repeated, and then pigs were euthanized for ex vivo studies to quantify renal microvascular (MV) density, angiogenic factor expression, and morphometric analysis. Renal hemodynamics were similarly blunted in all RVD pigs. PTRAs resolved stenosis but modestly improved RBF and GFR. However, combined PTRAs+ ELP-VEGF improved RBF, GFR, regional perfusion, plasma creatinine, asymmetric dimethlyarginine (ADMA), and albuminuria compared with PTRAs alone, accompanied by improved angiogenic signaling, MV density, and renal fibrosis. Greater improvement of renal function via coadjuvant ELP-VEGF therapy may be driven by enhanced MV proliferation and repair, which ameliorates MV rarefaction and fibrogenic activity that PTRAs alone cannot offset. Thus, our study supports a novel strategy to boost renal recovery in RVD after PTRAs.

A translational model of chronic kidney disease in swine.

Animal models of chronic kidney disease (CKD) are critical for understanding its pathophysiology and for therapeutic development. The cardiovascular and renal anatomy and physiology of the pig are virtually identical to humans. This study aimed to develop a novel translational model of CKD that mimics the pathological features of CKD in humans. CKD was induced in seven domestic pigs by bilateral renal artery stenosis and diet-induced dyslipidemia. Animals were observed for a total of 14 wk. Renal hemodynamics and function were quantified in vivo using multi-detector CT after 6, 10, and 14 wk of CKD. Urine and blood were collected at each time-point, and blood pressure was continuously measured (telemetry). After completion of in vivo studies, pigs were euthanized, kidneys were removed, and microvascular (MV) architecture (µCT), markers of renal injury, inflammation, and fibrosis were evaluated ex vivo. Additional pigs were used as controls ( n = 7). Renal blood flow and glomerular filtration were reduced by 50% in CKD, accompanied by hypertension and elevated plasma creatinine, albumin-to-creatinine ratio and increased urinary KIM-1 and NGAL, suggesting renal injury. Furthermore, 14 wk of CKD resulted in cortical and medullary MV remodeling and loss, inflammation, glomerulosclerosis, tubular atrophy, and tubule-interstitial fibrosis compared with controls. The current study characterizes a novel model of CKD that mimics several of the pathological features observed in human CKD, irrespective of the etiology. Current approaches only slow rather than halt CKD progression, and this novel model may offer a suitable platform for the development of new treatments in a translational fashion.

A Retroperitoneal Serous Cystadenoma of Müllerian Origin Masquerading as a Massive Renal Cyst.

A 78-year-old woman presented to the urology clinic with a large, symptomatic left-sided abdominal cyst that was believed to be renal in etiology for many years and that had been percutaneously drained 3 times previously with persistent regrowth. The patient underwent laparoscopic resection of this mass, which proved to be a completely distinct retroperitoneal cystic structure and was not renal in nature. Pathologic analysis ultimately revealed a rare occurrence: a benign retroperitoneal Müllerian serous cystadenoma. To our knowledge, this is the first report of such an entity "disguised" as a renal cyst.

Vascular Endothelial Growth Factor and Podocyte Protection in Chronic Hypoxia: Effects of Endothelin-A Receptor Antagonism.

BACKGROUND: Podocytes are major components of the filtration barrier and a renal source of vascular endothelial growth factor (VEGF). Chronic renovascular disease (RVD) progressively degrades the renal function, accompanied by podocyte damage and a progressive reduction in VEGF. We showed that the endothelin (ET) pathway contributes to this pathological process and ET-A (but not ET-B) receptor antagonism protects the kidney in RVD. We hypothesize that ET-A-induced renoprotection is largely driven by the protection of podocyte integrity and function. METHODS: To mimic the renal environment of chronic RVD, human podocytes were incubated under chronic hypoxia for 96 h and divided in untreated or treated with an ET-A or ET-B receptor antagonist. Cells were quantified after 96 h. Cell homogenates and media were obtained after 1, 24 and 96 h to quantify production of VEGF, anti-VEGF soluble receptor s-Flt1, and the expression of apoptotic mediators. A separate set of similar experiments was performed after addition of a VEGF-neutralizing antibody (VEGF-NA). RESULTS: Hypoxia decreased podocyte number, which was exacerbated by ET-B but improved after ET-A antagonism. Production of VEGF was preserved by ET-A antagonism, whereas s-Flt1 increased in hypoxic cells after ET-B antagonism only, accompanied by a greater expression of pro-apoptotic mediators. On the other hand, treatment with VEGF-NA diminished ET-A-induced protection of podocytes. CONCLUSION: ET-A antagonism preserves podocyte viability and integrity under chronic hypoxia, whereas ET-B antagonism exacerbates podocyte dysfunction and death. Enhanced bioavailability of VEGF after ET-A antagonism could be a pivotal mechanism of podocyte protection that significantly contributes to ET-A receptor blockade-induced renal recovery in chronic RVD.

Seminal vesicle abscess following prostate biopsy requiring transgluteal percutaneous drainage.

Transrectal ultrasound guided biopsy (TRUSB) of the prostate directly contaminates the prostate with rectal flora. Patients commonly receive fluoroquinolone (FQ) antibiotics to prevent infection. Infectious complications following TRUSB are increasing. The most common offending organism is Escherichia coli (E. coli), with isolates of this bacteria showing growing resistance to FQs. We present to our knowledge the first reported case of seminal vesicle abscess formation after TRUSB. The abscess was initially not seen on computed tomography and eventually treated with percutaneous drainage by a transgluteal approach. We review literature on infectious complications following TRUSB with implications for future antibiotic prophylaxis.

Unclamped hand-assisted laparoscopic partial nephrectomy for predominantly endophytic renal tumors.

PURPOSE: To describe our initial experience with unclamped laparoscopic hand-assisted partial nephrectomy for predominantly endophytic renal masses in the setting of relative contraindication to warm ischemia. MATERIALS AND METHODS: Unclamped laparoscopic hand-assisted partial nephrectomy was performed on eight consecutive patients from June 2009 to March 2010. All patients had predominantly endophytic renal masses with a preferential enhancing rim noted on the pre-operative computed tomography. The unclamped hand-assisted approach was utilized for no warm ischemia, minimal blood loss, and enhanced visualization of the tumor bed with improved operative exposure. RESULTS: Mean age of the participants was 55.8 years. All patients underwent unclamped hand-assisted partial nephrectomy (ie, zero ischemia). Mean estimated blood loss was 368.8 cc (range, 100 to 800 cc) and mean operation time was 236.9 minutes (range, 175 to 272 minutes). There were no intra-operative complications and no open conversions. There was one grade II (ileus with small pneumothorax) and one grade IV (pulmonary embolism) in the 90-day peri-operative period. There was one positive surgical margin, which was recognized intra-operatively. CONCLUSION: While our results are preliminary, we feel this technique provides superior visualization and adequate hemostasis while preserving oncologic efficacy and renal function in this patient population.

Surgical complications after robot-assisted laparoscopic radical prostatectomy: the initial 1000 cases stratified by the clavien classification system.

BACKGROUND AND PURPOSE: Complications after robot-assisted prostatectomy are widely reported and varied. Our goal was to determine the incidence of surgical complications resulting from robot-assisted laparoscopic radical prostatectomy (RALP) during the initial phase of a new robotics program that was developed by two surgeons without laparoscopic or robotic fellowship training. A secondary goal was to see if experience changed the incidence of complications with this technology. PATIENTS AND METHODS: A prospectively maintained database was used to evaluate the first 1000 consecutive patients who were treated with RALP from January 2004 to June 2009. The database was reviewed for evidence of complications in the perioperative period. All patients underwent robot-assisted laparoscopic radical prostatectomy by two surgeons. Complications were confirmed and supplemented by retrospectively reviewing the departmental morbidity and mortality reports, as well as the hospital records. The Clavien classification system, a standardized and validated scale for complication reporting, was applied to all events. The complication rate was determined per 100 patients treated and tested with logistic regression for a relationship with surgeon experience. RESULTS: Ninety-seven (9.7%) patients experienced a total of 116 complications; 81 patients experienced a single complication and 16 patients experienced ≥2 complications. The majority of complications (71%) were either grade I or II. The complication rate decreased with experience when the first 500 cases were compared with the latter 500 cases (P=0.007). All the data were reviewed retrospectively. Involvement of residents/fellows increased as primary surgeon experience improved. CONCLUSIONS: Complications after RALP are most commonly minor, requiring expectant or medical management only, even during the initiation of a RALP program. The complication rate improved significantly during the study period.

Rectal injury during robot-assisted radical prostatectomy: incidence and management.

PURPOSE: Rectal injury during robot-assisted radical prostatectomy is a rare but significant complication. Since the Clavien grading classification of complications does not include intraoperative injury without further sequelae, rectal injury may be underreported in the literature. We present what is to our knowledge the largest retrospective review to date of rectal injury and subsequent management. MATERIALS AND METHODS: We reviewed the records of 6,650 patients who underwent robot-assisted radical prostatectomy at a total of 6 institutions. Patient characteristics, perioperative parameters, pathological findings and rectal injury management were tabulated and analyzed for intraoperative predictors of outcome and subsequent management. RESULTS: A total of 11 rectal injury cases were identified of the 6,650 robot-assisted radical prostatectomies for a combined 0.17% incidence of rectal injury. Of rectal injuries 72.7% were identified intraoperatively and most did well with primary closure. Delayed recognition injury presented as rectourethral fistula without septic complications and required delayed fistula repair after primary diversion. We found no conclusive association of rectal injury with any patient parameter, intraoperative differences, pathological finding or surgeon experience. Posterior prostate plane dissection, including seminal vesicle dissection, is the crucial stage when rectal injury can occur and be identified. CONCLUSIONS: Our review of the records at 6 centers revealed a combined 0.17% incidence of rectal injury. This compares favorably to the incidence in modern open and laparoscopic radical prostatectomy series. No preoperative, intraoperative or pathological differences correlated with injury. Cases in which rectal injury was identified intraoperatively required fewer surgical repeat interventions but ultimately each group had acceptable long-term urinary and bowel function results.

Management of post-prostatectomy erectile dysfunction.

The management of post-prostatectomy erectile function has been debated since the nerve sparing radical prostatectomy was first introduced. A number of penile rehabilitation protocols have been proposed with varying degrees of success and patient satisfaction. My management of post-prostatectomy erectile dysfunction has evolved based on an honest and critical appraisal of the literature and my own experience and research. A review of major studies published on the topic of post-prostatectomy penile rehabilitation is included here, in addition to a critical evaluation of my own clinical practice. After evaluating the efficacy of these various approaches, it is clear to me that a nerve sparing procedure is only one of many factors involved in recovering erectile function. Moreover, in addition to assessing a patient's goals and their motivation for erectile function after prostatectomy, setting appropriate patient expectations is paramount to avoiding patient frustration. A frank evaluation and discussion with a patient and their partner is paramount to managing these expectations. A "one size fits all" approach is not appropriate. Herein, I discuss the evolution of my approach to managing post-prostatectomy erectile dysfunction.

Effect on sexual function of a vacuum erection device post-prostatectomy.

INTRODUCTION: Treatment of erectile dysfunction (ED) subsequent to bilateral nerve sparing robotic prostatectomy (BNSRP) with tadalafil plus a vacuum erection device (VED) may improve return of sexual function. MATERIALS AND METHODS: Men with prostate cancer who had BNSRP were randomized to receive tadalafil, 20 mg three times weekly, or tadalafil plus a VED, 10 minutes unbanded per day for at least 5 days weekly. Treatments started 1 month after surgery; clinic visits were at 1, 3, 6, 9 and 12 months. Patients were requested to attempt intercourse at least twice before each visit. At every visit patients completed the International Index of Erectile Function (IIEF-5) questionnaire and a penile hardness scale (1-4) and were questioned as to their ability to have vaginal penetration and intercourse to orgasm. RESULTS: Thirteen men started the combination regimen, and there were no dropouts; 10 patients started the tadalafil treatment, and three men dropped out. The mean IIEF-5 at months 6, 9 and 12 were significantly higher for the combination group, while the penile hardness scores were significantly greater for the combination group at 6 and 9 months. After 12 months 92% of combination patients responded yes to the vaginal penetration question versus 57% of the tadalafil group; corresponding figures were 92% and 29%, respectively, for intercourse to orgasm. Compliance to the VED was superior to that of tadalafil. CONCLUSION: Men with ED subsequent to BNSRP had a more rapid and complete return of sexual function when treated with tadalafil plus VED versus tadalafil alone.

Posterior rhabdosphincter reconstruction during robotic assisted radical prostatectomy: results from a phase II randomized clinical trial.

PURPOSE: Posterior rhabdosphincter reconstruction following radical prostatectomy was designed to improve early urinary continence. We executed a randomized clinical trial to test this conjecture in men undergoing robotic radical prostatectomy. MATERIALS AND METHODS: We conducted a phase II randomized clinical trial intended to detect a 25% difference in 3-month continence outcomes defined by a patient response of 0 or 1 to question 5 of the Expanded Prostate Cancer Index Composite questionnaire urinary domain, comparing standard running vesicourethral anastomosis (controls) to posterior rhabdosphincter reconstruction followed by standard running vesicourethral anastomosis (posterior rhabdosphincter reconstruction treated). Patients had clinically localized prostate cancer and were blinded. Surgeons were notified of computer randomization after prostate excision. Further continence outcomes were assessed by analysis of Expanded Prostate Cancer Index Composite questionnaire questions 1 and 12, International Prostate Symptom Score and 24-hour pad weights. Statistical significance was defined as p <0.05 RESULTS: A total of 94 patients were randomized, 47 to each arm. Preoperative clinical and functional variables were equivalent between study arms. There were no complications associated with either anastomotic technique. Of the 87 evaluable patients 62 (71.3%) met our 3-month continence definition. The null hypothesis was not rejected as 33 (81%) controls and 29 (63%) posterior rhabdosphincter reconstruction treated patients were continent at 3 months (chi-square p = 0.07, Fisher exact p = 0.1). Likewise there was no significant difference between arms in 24-hour pad weights (p = 0.14), International Prostate Symptom Score (p = 0.4), absence of daily leaks (p = 0.4) or perception of urinary function (p = 0.4). CONCLUSIONS: In this randomized clinical trial posterior rhabdosphincter reconstruction offered no advantage for return of early continence after robotic assisted radical prostatectomy.