Minimally Invasive Percutaneous Nephrolithotomy: Initial North American Experience.

Introduction and Objectives: The goal of this study is to evaluate the outcomes in a cohort of patients who underwent minimally invasive percutaneous nephrolithotomy (MIP) at a single institution from 2017 to 2019. Methods: Sixty patients at a single institution with two different surgeons underwent MIP from 2017 to 2019. The MIP technique uses a proprietary nephroscope with a "vacuum" technique for stone evacuation. Patients were identified who had postoperative CT scan imaging available for direct review. A prospectively maintained database was queried along with retrospective chart review to evaluate the stone-free rate defined as no stones on CT imaging. Preoperative, intraoperative, and postoperative variables were analyzed including initial stone size, access type (fluoroscopic vs ultrasonic), access location, operative positioning (supine vs prone), operative time, and 60-day complications. Results: Forty-six of 60 patients had CT imaging postoperatively that were reviewable. Of these, 43% (n = 20) were stone free as defined by no identifiable fragments seen, 11% (n = 5) had residual fragments 0 to 2 mm, 7% (n = 3) had residual fragments 2 to 4 mm, and 39% (n = 18) had residual fragments >4 mm. Mean initial stone size was 21 mm (1.9-84 mm). Sixty percent (n = 28) of the patients were discharged the same day as surgery. Fifty-one percent (n = 24) of access was achieved through ultrasound alone. Seventeen percent of patients (n = 8) had a complication within 30 days of surgery. All complications were Clavien III or lower with unplanned return to operating room rate of 2% (n = 1). Conclusions: We present North America's first single institution analysis of MIP cases with acceptable outcomes comparable with both retrograde intrarenal surgery and standard percutaneous nephrolithotomy. The exact role of MIP in renal stone disease needs to be determined by future studies that critically assess their outcomes.

Antibiotics are not necessary during routine cystoscopic stent removal: A randomized controlled trial at UC San Diego.

INTRODUCTION: Current American Urological Association (AUA) Best Practice Statement recommends antibiotic prophylaxis for cystoscopy with manipulation, including stent removal; although no Level 1b trials explicitly address prophylaxis for stent removal. We sought to determine the efficacy of prophylactic antibiotics to prevent infectious complications after stent removal. MATERIALS AND METHODS: Following institutional review board approval, patients undergoing removal of ureteral stent placed during stone surgery were recruited from July 2016 to March 2019. Patients were recruited at the time of stent removal and randomized to treatment (single dose 500 mg oral ciprofloxacin) or control group (no antibiotics). Telephone contact was attempted within 14 days of stent removal to assess for urinary tract infection (UTI) symptoms, antibiotic prescriptions, or Emergency Department visits. Primary outcome was UTI within 1 month of stent removal - defined by irritative voiding symptoms, fever or abdominal pain associated with positive urine culture (Ucx) (>100k colony-forming units/mL). RESULTS: Seventy-seven patients were enrolled, with 58 meeting final inclusion criteria for the analysis (33 treatment, 25 controls). No differences were seen with clinical and demographic variables, except a higher body mass index in the treatment group (P = 0.007). Positive Ucx rate before stone surgery (16.7% vs. 11.8%, P = 0.819) and at the time of stent removal (16.0% vs. 11.1%, P = 0.648) was not significantly different in treatment versus control groups, respectively. Primary outcome: No patients in either cohort developed symptomatic culture-diagnosed UTI within 1 month of stent removal. Of patients with documented phone follow-up (treatment n = 29, control n = 22), only one patient (control) reported any positive response on phone survey. CONCLUSIONS: We found a low infectious complication rate regardless of antibiotic prophylaxis use during cystoscopic stent removal. The necessity of antibiotics during routine cystoscopic stent removal warrants possible reevaluation of the AUA best practice statement.

Heparin and alkalinized lidocaine versus alkalinized lidocaine for treatment of interstitial cystitis symptoms.

INTRODUCTION: Interstitial cystitis (IC), sometimes referred to as IC/bladder pain syndrome, is a substantial health care problem. Once considered a rare, orphan disease, it is now believed to be relatively common. This pilot study was undertaken to determine if the combination of heparin and alkalinized lidocaine (heparin-lidocaine) was more efficacious than alkalinized lidocaine at relieving pain and urgency symptoms associated with IC and also capable of yielding higher lidocaine absorption. MATERIALS AND METHODS: A single blind study was conducted on 14 IC patients with a heparin-lidocaine combination versus alkalinized lidocaine instilled intravesically. In a separate study serum lidocaine levels for heparin-alkalinized lidocaine combination versus USP lidocaine only were determined by high performance liquid chromatography. RESULTS: Alkalinized lidocaine and heparin have been reported to provide relief from pain and urgency symptoms associated with IC. The heparin-lidocaine combination significantly reduced the % of bladder pain (38% versus 13%, p = 0.029) and urgency (42% versus 8% p = 0.003) compared to lidocaine. In addition the GAR was significantly better for the heparin-lidocaine combination at both 1 hr % improved (77% versus 50%, p = 0.04) and 24 hrs (57% versus 23%, p = 0.002) after study drug treatment. Serum lidocaine levels for the heparin-lidocaine combination were significantly higher compared to USP lidocaine (unalkalinized). The mean +/- SEM was 0.45 +/- 0.09 µg/mL and 0.20 +/- 0.05 µg/mL, respectively (p = 0.019). CONCLUSIONS: In this pilot study the heparin-lidocaine combination results in significantly better relief of IC symptoms compared to alkalinized lidocaine and the combination yields higher lidocaine absorption than USP lidocaine.

Role of urinary cations in the aetiology of bladder symptoms and interstitial cystitis.

OBJECTIVES: To identify and characterise urinary cationic metabolites, defined as toxic factors, in patients with interstitial cystitis (IC) and in control subjects. To evaluate the cytotoxicity of the urinary cationic metabolite fraction of patients with IC vs control subjects and of individual metabolites in cultured urothelial cells. SUBJECTS AND METHODS: Cationic fractions (CFs) were isolated from the urine specimens of 62 patients with IC and 33 control subjects by solid-phase extraction. CF metabolites were profiled using C18 reverse-phase high performance liquid chromatography (RP-HPLC) with UV detection, quantified by area-under-the-peaks using known standards, and normalized to creatinine. RP-HPLC and liquid chromatography (LC)-mass spectrometry (MS)/tandem MS (MS/MS) were used to identify major CF peaks. HTB-4 urothelial cells were used to determine the cytotoxicity of CFs and of individual metabolites with and without Tamm-Horsfall protein (THP). RESULTS: RP-HPLC analysis showed that metabolite quantity was twofold higher in patients with IC compared with control subjects. The mean (SEM) for control subjects vs patients was 3.1 (0.2) vs 6.3 (0.5) mAU*min/µg creatinine (P < 0.001). LC-MS identified 20 metabolites. Patients with IC had higher levels of modified nucleosides, amino acids and tryptophan derivatives compared with control subjects. The CF cytotoxicity was higher for patients with IC compared with control subjects. The mean (SEM) for control subjects vs patients was -2.3 (2.0)% vs 36.7 (2.7)% (P < 0.001). A total of 17 individual metabolites were tested for their cytotoxicity. Cytotoxicity data for major metabolites were all significant (P < 0.001): 1-methyladenosine (51%), 5-methylcytidine (36%), 1-methyl guanine (31%), N(4)-acetylcytidine (24%), N(7)-methylguanosine (20%) and L-Tryptophan (16%). These metabolites were responsible for higher toxicity in patients with IC. The toxicity of all metabolites was significantly lower in the presence of control THP (P < 0.001). CONCLUSIONS: Major urinary cationic metabolites were characterised and found to be present in higher amounts in patients with IC compared with control subjects. The cytotoxicity of cationic metabolites in patients with IC was significantly higher than in control subjects, and control THP effectively lowered the cytotoxicity of these metabolites. These data provide new insights into toxic factor composition as well as a framework in which to develop new therapeutic strategies to sequester their harmful activity, which may help relieve the bladder symptoms associated with IC.

Solubility of ammonium acid urate nephroliths from bottlenose dolphins (Tursiops truncatus).

Nephrolithiasis has been identified in managed populations of bottlenose dolphins (Tursiops truncatus); most of these nephroliths are composed of 100% ammonium acid urate (AAU). Several therapies are being investigated to treat and prevent nephrolithiasis in dolphins including the alkalization of urine for dissolution of nephroliths. This study evaluates the solubility of AAU nephroliths in a phosphate buffer, pH range 6.0-8.0, and in a carbonate-bicarbonate buffer, pH range 9.0-10.8. AAU nephroliths were obtained from six dolphins and solubility studies were conducted using reverse-phase high performance liquid chromatography with ultraviolet detection at 290 nm. AAU nephroliths were much more soluble in a carbonate-bicarbonate buffer, pH range 9.0-10.8 compared to phosphate buffer pH range 6.0-8.0. In the pH range 6.0-8.0, the solubility was 45% lower in potassium phosphate buffer compared to sodium phosphate buffer. When citrate was used along with phosphate in the same pH range, the solubility was improved by 13%. At pH 7 and pH 8, 150 mM ionic strength buffer was optimum for dissolution. In summary, adjustment of urinary pH alone does not appear to be a useful way to treat AAU stones in bottlenose dolphins. Better understanding of the pathophysiology of AAU nephrolithiasis in dolphins is needed to optimize kidney stone prevention and treatment.

Alkalinized lidocaine and heparin provide immediate relief of pain and urgency in patients with interstitial cystitis.

INTRODUCTION: It has been reported in an open-label study that the combination of alkalinized lidocaine and heparin can immediately relieve the symptoms of urinary urgency, frequency, and pain associated with interstitial cystitis (IC). This combination has also been reported to relieve pain associated with sex in patients with IC. AIM: The aim of this study was to corroborate these findings in a multicenter setting. METHODS: The study design was a multicenter prospective, double-blind, crossover, placebo-controlled trial. Each participant met all of the clinical National Institute of Diabetes and Digestive and Kidney Diseases criteria (excluding cystoscopy) for IC. Each patient received drug and control, in random order, within 48 hours of enrolling in the study. MAIN OUTCOME MEASURES: The primary outcome measure was percent change in pain score (11-point analog pain scale) 12 hours after receiving the drug or control. Secondary measures were the global assessment response (GAR) of symptoms and 12-hour average urgency reduction determined from 11-point urgency scales. RESULTS: Eighteen (18) patients completed the trial. The average reduction of pain over 12 hours was 21% for control and 42% for active drug (P = 0.0363). GAR was 13% for control and 50% for drug (P = 0.0137). Average urgency reduction was 13% for control and 35% for drug (P = 0.0328). CONCLUSIONS: The combination of alkalinized lidocaine and heparin provides up to 12 hours of relief from urgency and pain associated with IC. This combination provides significant immediate relief of symptoms for patients with IC.

A multi-site study confirms abnormal glycosylation in the Tamm-Horsfall protein of patients with interstitial cystitis.

PURPOSE: We confirm the single site observation of decreased sialylation and abnormal glycosylation of Tamm-Horsfall protein in patients with interstitial cystitis compared to control subjects. MATERIALS AND METHODS: Urine samples from 41 controls and 48 patients with interstitial cystitis from a total of 5 North American sites were obtained in blinded fashion as to participant status. Tamm-Horsfall protein was isolated from urine samples by salt precipitation. Protein content was determined by size exclusion chromatography and normalized to creatinine. Sialic acid was quantified by 1,2-diamino-4,5-methylene dioxybenzene (Sigma®) high performance liquid chromatography with fluorescence detection. Neutral and amino sugars were determined by high pH anion exchange chromatography with pulsed amperometric detection. N-glycans were labeled with 2-aminobenzamide and profiled using high pH anion exchange chromatography with fluorescence detection. Samples were also analyzed by matrix assisted laser desorption/ionization-time of flight mass spectrometry. Permethylated N-glycans were analyzed in the mass-to-charge ratio range of 3,000 to 6,000. RESULTS: There was no difference in the protein-to-creatinine ratio of Tamm-Horsfall protein from patients with interstitial cystitis vs controls (49.12 vs 46.4 mg/gm, p = 0.26). Sialic acid content (67 vs 77 nmol/mg Tamm-Horsfall protein, p = 0.025) and total monosaccharide content (590.9 vs 680.6 nmol/mg Tamm-Horsfall protein, p = 0.003) were significantly decreased in patients with interstitial cystitis vs controls. Results were supported by 2-aminobenzamide N-glycan profiling and mass spectrometry, which showed a 45% decrease in a major tetra-sialylated peak (mass-to-charge ratio 4,590) in Tamm-Horsfall protein from patients with interstitial cystitis compared to controls. CONCLUSIONS: These multisite data validate that abnormal glycosylation of Tamm-Horsfall protein occurs in patients with interstitial cystitis and may have a role in interstitial cystitis causation.

Defective Tamm-Horsfall protein in patients with interstitial cystitis.

PURPOSE: Normal urinary Tamm-Horsfall protein shows a urothelial cytoprotective effect against potentially toxic compounds in urine that may injure the urothelium and cause bladder disease. One such disease is interstitial cystitis. In patients with interstitial cystitis this protective effect is decreased. We hypothesized that a difference in Tamm-Horsfall protein in patients with interstitial cystitis exists that may be involved in disease pathogenesis. MATERIALS AND METHODS: Using enzyme-linked immunosorbent assay the urinary Tamm-Horsfall protein concentration was determined in patients with interstitial cystitis and control subjects. Sialic acid content was measured by high performance liquid chromatography based assay. The structure of the protein glycosylation chains was analyzed using matrix assisted laser desorption/ionization-time of flight mass spectrometry. RESULTS: The mean Tamm-Horsfall protein concentration was not significantly different in patients with interstitial cystitis and controls (28.8 vs 28.2 mg/l urine and 36.8 vs 36.7 microg/mg creatinine, respectively, p = 0.6). The total mean sialic acid content of Tamm-Horsfall protein was almost 2-fold lower in 22 patients with interstitial cystitis compared with that in 20 controls (46.3 +/- 4.3 vs 75.3 +/- 4.1 nmol sialic acid per mg Tamm-Horsfall protein, respectively, p <0.0001). On matrix assisted laser desorption/ionization-time of flight mass spectrometry N-glycans released from Tamm-Horsfall protein revealed lower molecular weight di-antennary N-glycan structures and a resulting decrease in the number of terminal sialic acid residues in 10 patients with interstitial cystitis relative to those in 10 controls. CONCLUSIONS: Tamm-Horsfall protein is qualitatively different in patients with interstitial cystitis compared to controls. These data suggest that altered Tamm-Horsfall protein may be involved in interstitial cystitis pathogenesis and it may be useful for clinical diagnosis.

Preliminary report on analysis of bladder-wall vasculature using conjunctival microvascular analysis in patients with and without transitional-cell carcinoma.

PURPOSE: To develop a technique to analyze the bladder microvasculature during cystoscopy to assess the conjuctival microvascular morphology at the capillary level. This technique could be an adjunct to visual examination of the bladder during cystoscopy for diseases that are presumed to affect the vasculature. PATIENTS AND METHODS: Subjects with transitional-cell carcinoma (TCC) were chosen because of their frequency of cystoscopy. A total of 12 male patients, ages 45 to 80 years, underwent cystoscopy: four without TCC and eight with TCC by bladder biopsy. The images were digitally recorded and enhanced using a custom image-analysis system. The blood vessel length (VL) and diameter (VD) and blood vessel volume (BVV) were measured. RESULTS: The VD was significantly greater in TCC than in non-TCC patients only in the lower-order vessels. The VL was significantly longer in TCC than in non-TCC, again in the lower-order vessels. In the higherorder vessels, the VL was significantly shorter in TCC than in non-TCC. The BVV in the lower-order vessels was significantly greater in TCC than in non-TCC patients. CONCLUSIONS: Differences exist in the morphology of surface microvessels between TCC and non-TCC bladders. Using the current technique, capillaries (VD < 10 microm) are not visible, so refinement of imaging and recording technologies is required to measure capillaries in order to simulate microvascular morphometry in the conjuctiva.

Quantifying symptoms in men with interstitial cystitis/prostatitis, and its correlation with potassium-sensitivity testing.

OBJECTIVE: To determine whether men previously diagnosed with prostatitis also have pathology originating in the bladder. PATIENTS, SUBJECTS AND METHODS: We administered the pelvic pain and urgency/frequency (PUF) questionnaire and the potassium-sensitivity test (PST) to 50 patients with prostatitis presenting in urological and primary care, and to 14 controls. In a separate control group of 22 men, the urethra was irrigated with KCl or NaCl (11 each) before and after experimental injury of the urethral mucosa. RESULTS: All 50 patients with prostatitis had PUF scores of > or = 7; 77% were positive for the PST. All 14 controls had PUF scores of 1 or 0 and a negative PST. In the urethral irrigation study in controls, KCl but not NaCl provoked urethral pain after mucosal injury. Before injury, neither KCl nor NaCl caused symptoms. CONCLUSION: The high rate of positive PST in patients with "classic" prostatitis indicates that pathology originating in the bladder may be an important source of symptoms in most. In patients with prostatitis and female patients with interstitial cystitis, symptoms may arise not from separate disease entities but from a continuum of epithelial dysfunction and potassium cycling that may be present throughout the lower urinary tract.

Intraoperative mapping of renal lymphatic drainage: technique and application in a porcine model.

BACKGROUND AND PURPOSE: The use of lymphadenectomy in renal-cell carcinoma (RCC) is controversial. Proponents argue that lymphadenectomy improves survival, whereas opponents challenge the procedure on the basis of its morbidity and the variable lymphatic drainage of the kidney. Intraoperative gamma probes have been used to guide resection of radiolabeled sentinel nodes in cancers of the breast, penis, and head and neck and in melanoma. Our goal in applying this technique to RCC is to improve detection and to limit sampling of lymph nodes during lymphadenectomy. This preliminary study in a porcine model evaluated the feasibility and transit time of radiolabeled tracer injected into the kidney. MATERIALS AND METHODS: Data were collected on four 40-kg Yorkshire pigs. The right kidney was exposed through a flank incision. Using both blue dye and technetium-99m, mapping and resection of the sentinel lymph nodes was performed with the assistance of an intraoperative gamma probe (Neoprobe). Remote cervical lymph nodes were utilized as controls. Vascular counts along the carotid vessels were obtained to confirm that the radioisotope was not being dispersed systemically. RESULTS: Within 10 minutes of renal injection of the tracer, excised sentinel lymph nodes demonstrated significant radioactive counts compared with controls. Vascular counts confirmed that radioisotope tracer did not enter the venous circulation. CONCLUSIONS: Sentinel lymph node sampling using a gamma probe and blue dye appears to be feasible in the porcine kidney. Further studies using this technique in humans will evaluate the impact of selective lymphadenectomy on survival in RCC.

Small intestinal submucosa as a tunica albuginea graft material.

PURPOSE: We evaluated the morphological, immunological and functional response to small intestinal submucosa grafting of the tunica albuginea to determine its potential as a grafting material for penile surgery. MATERIALS AND METHODS: Male New Zealand White rabbits underwent a sham procedure (6) or tunical excision and grafting with small intestinal submucosa (6). The erectile response to the intracavernous vasoactive agents sodium nitroprusside plus a papaverine, phentolamine and prostaglandin E1 combination (Sigma Chemical Co., St. Louis, Missouri) was evaluated 45-day postoperatively. The area under the graft was evaluated for stromal collagen and smooth muscle content by Masson's trichrome stain. Protein expression of smooth muscle specific alpha-actin and the inflammatory markers inducible nitric oxide synthase (NOS) and transforming growth factor-beta1 (TGF-beta1) was evaluated by immunohistochemical methods. Total RNA was extracted from the corpora cavernosum underlying the small intestinal submucosa graft and reverse transcriptase-polymerase chain reaction (RT-PCR) was done using an Access system (Promega, Madison, Wisconsin) with gene specific primers for inducible NOS, TGF-beta1 and vascular endothelial growth factor (VEGF). RESULTS: Grafting of the tunica albuginea with small intestinal submucosa had no significant effect on the magnitude or duration of the erectile response to intracavernous vasoactive agents. Histological examination demonstrated no inflammatory changes in the tunica albuginea or corporeal tissue underlying the area of the small intestinal submucosa graft and there was no appreciable alteration in smooth muscle or collagen content. The 2 groups showed intense positive immunostaining to alpha-actin. Weak expression of TGF-beta1 predominantly associated with smooth muscle fibers was identified in the 2 groups of rabbits by immunostaining and RT-PCR. No significant inducible NOS was detected by immunostaining or RT-PCR in either group. Strong VEGF expression was observed in grafted rabbits. The most noticeable (3-fold) increase in expression was detected in splice variant 165. CONCLUSIONS: Small intestinal submucosa grafting of the tunica albuginea preserves the duration and magnitude of the erectile response to vasoactive agents. This type of tunical grafting does not stimulate a significant inflammatory response, or cause corporeal fibrosis or loss of cavernous smooth muscle content. Stimulating VEGF may facilitate wound healing and the maintenance of normal erectile function.