Go With the FLow: Managing Common Diseases of the Urinary Tract

Educational Objectives

The goal of this program is to improve the management of common diseases of the urinary tract, including treatment of geriatric nocturia, phytotherapy for lower urinary tract symptoms (LUTS), sacral neuromodulation (SNM) therapy, and antibiotic prophylaxis for urinary tract infections (UTIs) in women and children. After hearing and assimilating this program, the clinician will be better able to:

1.   Identify coexistent medical conditions that maycontribute to nocturia in older male patients.

2.   Review the agents available for the treatment of nocturia and their efficacy as shown in recent studies.

3.   Explain the problems with trials of phytotherapy and list some of the agents used in the alternative treatment of LUTS.

4.   Describe the peripheral nerve evaluation (PNE) and tined lead staged implantation procedure used in SNM therapy .

5.   Discuss recent trials of antibiotic prophylaxis for the prevention of recurrent UTIs in women and children.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Johnson has been a consultant for Johnson & Johnson Services, Pfizer, and Fleming Pharmaceuticals. Dr. Nitti is a preceptor for Ethicon. Drs. Johnson and Wiener discuss off-label use of a therapy, product, or device in their lectures. Dr. Nieh and the planning committee reported nothing to disclose.

Ackowledgements

Drs. Johnson, Nieh, and Nitti were recorded at Advances in Urology, presented December 12-13, 2008, in Atlanta, GA, and sponsored by the Emory University School of Medicine. Dr. Wiener spoke at the 41st Annual Duke Urologic Assembly, held March 7-10, 2009, in Las Vegas, NV, and sponsored by the Duke University School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this pro­gram.

Geriatric Nocturia and Other Lower Urinary Tract Symptoms (LUTS)

Ted M. Johnson II, MD, Associate Professor of Medicine and Director, Division of Geriatric Medicine and Gerontology, Emory University School of Medicine, Atlanta, GA

Pathophysiology of nocturia: age has profound effect on LUTS (odds ratio [OR] for having ³2 episodes of nocturia per night 154.6 for men and 9.1 for women 70-79 yr of age, compared to that at 18-29 yr of age); reduced bladder capacity; nocturnal polyuria; sleep disruption

Comorbidities: speaker’s study evaluated multimodal treatment of nocturia; 55 men (average age »65 yr); many pa­tients had coexistent medical conditions potentially contributing to nocturia (eg, congestive heart failure [CHF]; diabetes; sleep latency ³30 min; pitting peripheral edema; daytime frequency; hypertension); patients who have nighttime nondipping of blood pressure more likely to have nocturia; nearly all patients in study had American Urological Association (AUA)-7 symptom inventory >8

Sleep apnea: treatment can reduce nocturia; speaker screens patients for heavy snoring and apneic episodes; en­courage patients who do not respond to pharmacologic or behavioral therapy to have sleep studies if they screen positively

Nocturia vs bother: data from recent study of medical treatment of benign prostatic hyperplasia (BPH) suggests pos­sible correlation between number of nightly episodes of nocturia and amount of bother; speaker’s study looked at characteristics of patients with 2 to 3 episodes of nocturia who had low or high bother; contributing factors in­cluded time it took to return to sleep, and level of fatigue in morning

Drug therapy for nocturia: desmopressin (DDAVP; produces largest net nightly episode reduction); behavioral therapy; bladder relaxants (not effective as single-agent therapy; may be useful in patients who have urgency and accidents at night); a-blockers (poor results )

Medical Therapy of Prostatic Symptoms (MTOPS) study: analyzed efficacy of placebo, doxazosin, finasteride, and combination therapy in reduction of nocturia; all treatments statistically better than placebo; however, net dif­ference between placebo and therapy only »0.2 episodes per night

Kaplan study (2006): looked at tolterodine or tamsulosin as single agents or in combination; only significant differ­ence combination therapy vs placebo (»0.24 episodes per night)

Caveats about DDAVP in older adults: off-label use of DDAVP  causes patient to retain water (effect); duration of effect of oral DDAVP too long and unpredictable in 20% to 30% of older patients; patients develop water intoxica­tion and sodium level drops; patients >65 yr of age with low serum sodium at baseline have 75% chance of devel­oping hyponatremia when treated with DDAVP; side effects  —  unpredictable, so monitoring important; differ by age and baseline sodium

Behavioral therapy: in study by speaker et al of behavioral and drug therapy vs placebo for nocturia in older women with urge and/or mixed urinary incontinence (UI), behavioral therapy proved most effective  (however, number of women who had reduction of ³1 episodes only »23%)

Phytotherapy as Alternative Treatment for LUTS

Peter T. Nieh, MD, Associate Professor of Urology, Emory University School of Medicine, Atlanta, GA

Study data: users  —  more likely men 51 to 60 yr of age; white (2:1 compared to blacks); holders of college and grad­uate school degrees; >50% of users also take traditional prescription medications for LUTS; a-blockers more effec­tive (6-point drop in symptom scores; 4-point drop with finasteride); patients on phytotherapy had »43% improvement; however, placebo effect usually 40%

Problems with phytotherapy trials: small numbers of patients; relatively short follow-up (»6 mo); most not ran­domized; many do not have placebo group; since passage of Dietary Supplements Health and Education Act, herbs defined as dietary supplements (do not have to prove efficacy or show safety before placing on market; product contents do not have to match labeling)

Saw palmetto (Serenoa repens): used primarily for urinary symptoms associated with BPH; side effects  —  incidence »2%; primarily gastrointestinal (GI); Cochrane meta-analysis  —  »3139 patients from »21 randomized trials lasting 4 to 48 wk ( »18 double-blinded); found that Serenoa repens improves urinary symptom scores by 1.41 points, noc­turia by 0.76 (0.3-0.5 with a-blockers), and urinary peak flow rate (UFR) by 1.8 mL/sec; improvement comparable to that with finasteride, with fewer side effects; study  —  patients randomized to receive Serenoa repens or tamsulo­sin (eg, Flomax) alone, or in combination; at 6 mo, no difference between groups as shown by UFR or symptom scores; recent study of Serenoa repens and BPH  —  longest follow-up (1 yr); found no significant difference in symptom scores, UFR, prostate volume, residual urine volume, QOL, and prostate-specific antigen (PSA) levels

African plum tree (Pygeum africanum): Cochrane meta-analysis  —  >1500 patients in 18 trials (6 placebo-con­trolled); showed moderate improvement in symptoms (nocturia) and UFR

Pumpkin seed (Cucurbita pepo): in randomized placebo-controlled trial with 1-yr follow-up, international prostate symptom score (IPSS) improved by 6.8 points (5.6 with placebo)

Rye pollen (Secale cereale): used in 2 placebo-controlled, and 2 short comparative trials; decreased nocturia more than placebo, but no improvement seen in UFR, residual urine volume, or prostate size

Stinging nettle (Urtica dioica): often used in combination with Serenoa repens; in randomized trial comparing com­bination to finasteride, symptom score and UFR improved

South African star grass (Hypoxis rooperi): produced “impressive results” in trials in mid 1990s; concluded that product produced better results than a-blockers, 5-a reductase inhibitors, or combination; Cochrane meta-analysis  —  showed improvement in IPSS by »5 points and  in peak flow rate by  »4 mL/sec

Quercetin: bioflavonoid with anti-inflammatory activity; seems to inhibit inflammatory cytokines; some interest in using it in treatment of chronic prostatitis and chronic pelvic pain syndrome, as well as BPH (decreases symptom scores)

Concluding comments: majority of these agents thought to have anti-inflammatory effects; most sold in combina­tion, which makes them fairly cost-effective; summary  —  selected phytotherapy comparable to a-blockers, 5-a re­ductase inhibitors, or combination; agents seem to have fewer side effects and comparable cost

Update on Neurostimulation

Victor W. Nitti, MD, Professor and Vice Chair, Department of Urology, and Director of Fellowship in Female Pelvic Medicine and Reconstructive Surgery, New York University Langone Medical Center, New York, NY

Neuromodulation of LUT and pelvic floor: mechanism of action not fully understood; implies modification of sen­sory and/or motor functions through electrical stimulation; urodynamic changes often minimal, but symptomatic improvement common

Sacral neuromodulation (SNM): because of infection, inflammation, anatomic abnormalities, and neurologic dis­ease, involuntary reflex mechanisms arise and interfere with voluntary control of micturition; SNM helps to restore coordination between nerves and muscles; Food and Drug Administration (FDA)-approved indications  —urinary urgency and frequency; urge UI [UUI]; nonobstructive urinary retention

Peripheral nerve evaluation (PNE): office procedure; uses temporary lead (single external wire electrode taped in position); in speaker’s experience, PNE difficult (patients unable to keep electrode in place), resulting in inadequate test results

Staged implant: tined lead; inserted in hospital (4 electrodes of lead placed through S3 foramen); each electrode stimulated to test for motor and sensory response; test patients for 2 to 4 wk; patient comes out of operating room (OR) with lead buried and temporary extension wire coming out skin; much more sturdy and durable than PNE; pa­tient sent home; adjustments can be made to leads to achieve optimal response; depending on response, patient re­turns for removal of lead or installation of implantable generator (IPG)

PNE vs staged implant: PNE success rates »50%; £33% of positive PNEs do not have continued response after IPG placement; success rates for tined lead staged implantation »75%; urodynamic changes more pronounced in staged procedure

Unilateral vs bilateral stimulation: in prospective randomized crossover study, no statistically significant difference seen in voiding symptoms between groups; in recent retrospective study, patients with bilateral leads had each lead tested separately during trial period; these patients had significantly higher rate of progression to stage II implanta­tion, compared to patients who had unilateral leads; progression to implantation based on ³50% improvement of subjective symptoms and objective parameters during 2-wk trial

Long-term outcomes: in patients with UUI, clinical success rate approaches »80% after 12 mo of SNM therapy (re­sults similar for patients with urinary retention); response decreases over time in some patients; however, study by Siegel et al reported relative success rate of »59% at 3 yr; another recent study reported 5-yr success rates of »68% for UUI, »56% for frequency and urgency, and »71% for retention; complications  —»60 patients required reopera­tion for pain from stimulation or at IPG site; sensation of electrical shock; undesirable change in voiding function; lead migration; problems with device

Other applications: persistent overactive bladder (OAB) symptoms after urethrolysis  —  study reported »75% re­sponse rate to InterStim therapy at 15 to 16 mo in women whose OAB symptoms failed to respond to urethrolysis

Pudendal nerve stimulation: study of pudendal vs SNM; »30 subjects had standard tined lead plus pudendal lead placed via posterior approach; each lead tested in blinded randomized fashion for »10 days; of those who chose to have permanent implant, 80% said pudendal nerve stimulation worked better

Posterior tibial nerve stimulation (PTNS): hypothesis that stimulating posterior tibial nerve once weekly for »30 min will produce good response; in Govier et al study of PTNS, 71% of patients felt to be “responders”; study by Vandoninck et al also showed reasonable results;  most studies  done without sham arm, so speaker unsure how ef­fectively therapy can be evaluated; maintenance therapy necessary to sustain symptom reduction

Prophylactic Antibiotics in Children and Women

John S. Wiener, MD, Associate Professor of Surgery and Pediatrics and Head, Section on Pediatric Urology, Duke University School of Medicine, Durham, NC

Urinary Tract Infections (UTIs) in Children

Antibiotic prophylaxis:  review of 19 trials  —  most studies poor; »12 agents used (trimethoprim-sulfamethoxazole [TMP-SMZ] and nitrofurantoin [NF] most common); only 2 good studies Lohr et al  —  crossover study of 18 girls using NF; 25 UTIs without antibiotics vs 2 with antibiotics; 14 symptomatic UTIs in group without treatment, none with treatment; Smellie et al  —  unblinded randomized controlled trial (RCT) of 47 children treated with TMP-SMZ or NF; 50% had UTIs in group without treatment vs zero with treatment

Recent RCTs of children with vesicoureteral reflux (VUR): Montini et al (2004)  —found no difference in inci­dence of febrile UTIs, but fewer total UTIs; Garin et al (2006)  —  no difference in children with VUR (in those without VUR, incidence of UTIs 13% with placebo vs 2% with treatment); Roussey-Kesler et al (2006)  —  no dif­ference in total or febrile UTIs (might be difference in boys with grade 3 VUR); Montini (2008), Pennesi (2008)  —  no difference in incidence of pyelonephritis; Cheng (2008)  —  fewer breakthrough UTIs; greater resistance seen with cephalosporins

Summary: no consensus on use of antibiotics in children with VUR; cannot view recurrent UTI in isolation (voiding dysfunction and constipation often treated at same time)

Antibiotic Prophylaxis in Women

UTIs in women: »60% have £1 UTI in lifetime; »10.8% of women in United States report ³1 UTI in past year; 20% to 30% of women with history of UTI have recurrent UTIs; definition of recurrent UTIs  —  3 UTIs in »12 mo or 2 UTIs in »6 mo

Cochrane meta-analysis of RCTs: looked at uncomplicated UTIs in nonpregnant women with duration of therapy £6 mo (≈10 placebo-controlled trials and »10 antibiotic vs antibiotic studies met criteria; variety of agents used (NF; TMP-SMZ or TMP alone; cephalosporins; fluoroquinolones); variable study protocols; recurrence classified as microbiologic or clinical agents

Summary of outcomes: most agents showed reduction in clinical and microbiologic recurrences; effect short dura­tion (treatment groups equal to placebo after stopping prophylaxis); 12 mo maximum duration tested; drop-out rate high in all studies; side effects common (£20%)

Suggested Reading

Abseil SR et al: Sacral neuromodulation: cost considerations and clinical benefits. Urology 70:1069, 2007; Albert X et al: Anti­biotics for preventing recurrent urinary tract infection in non-pregnant women. Cochrane Database Sits Rev (3):CD001209, 2004; Burgio KL et al: Behavioral vs drug treatment for urge urinary incontinence in older women: a randomized controlled trial. JAMA 280(23):1995, 1998; Dvorkin L, Song KY: Herbs for benign prostatic hyperplasia. Ann Pharmacother 36:1443, 2002; Ed­gar AD et al: A critical review of the pharmacology of the plant extract of Pygeum africanum in the treatment of LUTS. Neurou­rol Urodyn 26:458, 2007; Hagerty JA et al: Hizli F, Uygur MC: A prospective study of the efficacy of Serenoa repens, tamsulosin, and Serenoa repens plus tamsulosin treatment for patients with benign prostate hyperplasia. Int Urol Nephrol 39:879, 2007; Hussain Z et al: Neuromodulation for lower urinary tract dysfunction--an update. Scientific World Journal 7:1036, 2007; Johnson TM et al: Effects of behavioral and drug therapy on nocturia in older incontinent women. J Am Geriatr Soc 53:846, 2005; Johnson TM et al: Medical Therapy of Prostatic Symptoms Research Group. The effect of doxazosin, finasteride and com­bination therapy on nocturia in men with benign prostatic hyperplasia. J Urol 178:2045, 2007; Montini G et al: Antibiotic treat­ment for pyelonephritis in children: multicentre randomised controlled non-inferiority trial. BMJ 335:386, 2007; Nitti VW et al: Efficacy and tolerability of tolterodine extended-release in continent patients with overactive bladder and nocturia. BJU Int 97:1262, 2006; Ouslander J et al: The dark side of incontinence: nighttime incontinence in nursing home residents. J Am Geriatr Soc 41:371, 1993; Patel AK et al: Medical management of lower urinary tract symptoms in men: current treatment and future ap­proaches. Nat Clin Pract Urol 5:211, 2008; Peeren F et al: Sacral nerve stimulation: Interstim therapy. Expert Rev Med Devices 2:253, 2005; Pham K et al: Unilateral versus bilateral stage I neuromodulator lead placement for the treatment of refractory void­ing dysfunction. Neurourol Urodyn 27:779, 2008; Rembratt A et al: Desmopressin treatment in nocturia; an analysis of risk fac­tors for hyponatremia. Neurourol Urodyn 25:105, 2006; Roussey-Kesler G et al: Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study. J Urol 179:674, 2008; Smellie JM et al: Controlled trial of prophylactic treatment, in childhood urinary-tract infection. Lancet 2:175, 1978; Sökeland J et al: Combination of Sabal and Urtica extract vs. finasteride in benign prostatic hyperplasia (Aiken stages I to II). Comparison of therapeutic effectiveness in a one year double-blind study]. Urologe A 36:327, 1997; Tacklind J et al: Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2:CD001423, 2009; van Exel NJ et al: TRI­UMPH Pan-European Expert Panel. Medical consumption and costs during a one-year follow-up of patients with LUTS sugges­tive of BPH in six European countries: report of the TRIUMPH study. Eur Urol 49:92, 2006; Vaughan CP et al: A multicomponent behavioural and drug intervention for nocturia in elderly men: rationale and pilot results. BJU Int 104:69, 2009; White WM et al: Incidence and predictors of complications with sacral neuromodulation. Urolog 73:731, 2009.