Ten Things Pediatricians Need to Know About Urology

Tony Khoury MD FRCSC FAAP Walter R. Schmid Professor of Pediatric Urology Professor, Department of Urology University of California, Irvine Head of Pediatric Urology Children's Hospital of Orange County

1. Prenatal Hydronephrosis Antenatal Hydronephrosis

 Detected by U/S in 1/400 pregnancies  Represents 30% of prenatal anomalies  Postnatal persistence in 50%

PUV Duplex Single kidney 10% 10% 2%

VUR Unilateral 26% 37%

Bilateral 15%

Antenatal Hydronephrosis Ultrasound - Prenatal

 AP diameter – SFU grading  Empty bladder  20 weeks or more

Normal Calyx

Grade 2 – central split No Calyx confined to border, normal Blunted Calyx parenchyma Grade 1 – slight central split Grade 3 – wide split, pelvis SFU Consensus outside renal border, caliectasis, normal parenchyma

–Grade 4 – large calyces, thin parenchyma Bulging Calyx »< half contralateral, or <4mm Normal Fetal AP diameter

Week MM 16 4 mm 24 6 mm 28 7 mm 40 10 mm

Antenatal Hydronephrosis Ultrasound - Postnatal

 Careful with the interpretation of the newborn US  relative dehydration  Cortical echogenicity Antenatal Hydronephrosis Ultrasound - Prenatal

Outcomes  Grade 1  97% spontaneous resolution  20-30% incidence of VUR (with any degree of prenatal hydronephrosis)  Grade 2  80% spontaneous resolution  10% OR  Grade 3  30% OR  Grade 4  ≈90% OR

AP Diameter as an Indicator for Pyeloplasty Key points AHN

 Majority resolve, early delivery “never”

 Infections rare

 VCUG only indicated if ureter dilated or bladder abnormal

 No need for Abx

 Insist on proper radiology interpretation

2. Incontinence

The Poor Bladder

10 11

Courage Kindness Generosity

Intelligence Wisdom Creativity

12 Normal Bladder Function

 Low pressure filling

 Low pressure storage

 Perfect continence

 Periodic voluntary expulsion (at low pressure)

 Resist infection

Detrusor Muscle Properties

Contractile properties well suited for either urine storage or release

Smooth Muscle Connective Tissue NormalNormal ReflexReflex

Cortical Inhibition

(+) Low Pressure Stretch Receptors Storage

Bladder Filling

Urethral Control Mechanism

Smooth muscle maintains tone with relatively little expenditure of energy Striated muscle for emergencies Holding Reflex Sacral - +  reflex Voiding Dysfunction + + Wein’s Functional Classification  Failure to Store  Because of Bladder +  Because of Urethra  Combined -

 Failure to Empty  Because of Bladder -  Because of Urethra  Combined +

Diagnostic Studies

 Bladder Diary (capacity, urgency, frequency, incontinence)

 Uroflow and PVR Simple Measures to Correct Incontinence

 Timed voiding: vibrating alarm Watch

 Increase water intake

 Correct constipation

Sensory Urgency

 Daytime frequency

 No Nocturia

 No incontinence

 Self limiting

 Water

 Rx Constipation 3. Nocturnal Enuresis

Incidence

5 to 7 million children in the US Boys:Girls 3:1

80% primary 15% resolve / year Hereditary Factors

Norgaard JP, Djurhuus JC, Watanabe H, Stenberg A, Lettgen B. Experience and current status of research into the pathophysiology of nocturnal enuresis. Br J Urol 1997;79:825-35.

Etiology - Dandelions

 Anecdotal reports and folk wisdom say children who handle dandelions can end up wetting the bed.  Dandelions are reputed to be a potent diuretic.  English folk names for the plant are "peebeds" and "pissabeds”. In  French dandelions are called  pissenlit, which means "urinate in bed"; likewise "piscialletto", an Italian folkname, and "meacamas" in Spanish. Pathophysiology

Nocturnal Polyuria

Disturbance at the Brainstem Nocturnal Detrusor Level High Arousal Overactivity Thresholds

 The bedwetting child is regarded as a “deep sleeper”  Supported by  Universal parental observation that their enuretic children are difficult to awaken (Nevéus T, Hetta J, Cnattingius S, Tuvemo T, Läckgren G, Olsson U, Stenberg A (1999) Depth of sleep and sleep habits among enuretic and incontinent children. Acta Paediatr 88:748–752)

 Studies on objective arousal thresholds (Wolfish NM, Pivik RT, Busby KA (1997) Elevated sleep arousal thresholds in enuretic boys: clinical implications. Acta Paediatr 86:381–384)  Sleep electroencephalogram (EEG) of enuretic children not different from that of dry children. NE and Sleep Disturbances

 Enuresis may be caused by heavy snoring or sleep apneas due to adenotonsillar hypertrophy.  Possible explanations  The constant arousal stimuli from the obstructed airways causes paradoxically high arousal thresholds  The negative intrathoracic pressure causes polyuria via increased secretion of the atrial natriuretic peptide

Umlauf MG, Chasens ER (2003) Sleep disordered breathing and nocturnal polyuria: nocturia and enuresis. SleepMed Rev 7:403–411

The Marvel of the Hibernating Bear

 Urine production  Muscle mass  Bones  Boredom! Alterations in Vasopressin Secretion and Nocturnal Urine Production

 About 50% less urine is normally excreted during the night than during the day.

 Due to a circadian rhythm of plasma arginine vasopressin (AVP)

Etiology : ADH

Delay in achieving circadian rise in arginine vasopressin

nocturnal polyuria

overwhelms the bladder No significant difference in nocturnal urine osmolality between enuretic and nonenuretic children at any age

Kawauchi and Watanabe (1993)

Nocturnal Polyuria

Weak evidence for presence of true nocturnal polyuria in MSNE

Van Hoeck K, Bael A, Lax H, et al. Urine output rate and maximum volume voided in school-age children with and without nocturnal enuresis. J Pediatr 2007; 151:575–580. NormalNormal ReflexReflex

Cortical Inhibition

(+) Low Pressure Stretch Receptors Storage - Bladder Filling + Evaluation

 General

 Child and parent attitude toward NE

 Confirm that it is PMNE

 BBD: Bladder Bowel Diary, Uroflow

 Frequency of NE: number per week and per night

 R/O other conditions: DI, CRF, PUV, UTI

Treatment

Remember the Natural History!! Timing of Treatment

 Treatment is rarely successful before Age 7  15% of children are enueretic at age 5

 The child needs to be truly motivated for treatment to succeed

 Who is more interested in dryness: the parent or the child?

Treatment

 Behavioral Interventions  Alarms  Medications

Important treatment aim is to protect and improve self-esteem. Counsel the parents, warn about psychological damage caused by pressure, shaming, or punishment for a condition the child cannot control Treatment Behavioral Interventions

 Reducing fluid intake in the evening  Reduces incontinence volume  Rarely impacts frequency of wetting episodes

 Lifting: ineffective

 Reward System

 Responsibility to induce motivation Treatment - Medications

Dry Desmopressin Response Partial Response

No Response

Desmopressin probably unsuccessful: • If maximum voided volumes <70% of the expected bladder capacity • No nocturnal polyuria (nocturnal urine production less than 130% of the expected bladder capacity).

Desmopressin + Alarm Desmopressin + Anticholinergic

 Patients with MNE who did not respond to desmopressin alone

 Reduction in the number of wet nights compared to desmopressin alone

Austin PF, Ferguson G, Yan Y, et al. Combination therapy with desmopressin and an anticholinergic medication for nonresponders to desmopressin for monosymptomatic nocturnal enuresis: randomized, double-blind, placebocontrolled trial. Pediatrics 2008; 122:1027–1032.

Desmopressin Downside

The therapeutic effect of DDAVP is temporary, and once treatment is stopped 50% to 90% of children relapse and resume their original pattern of wetting (Kahan et al, 1998). DDAVP

Ideal for Overnight Camps and Sleepovers

Behavior Modification should be considered the first-line approach to the management of enuresis Reward System

Stickers Rewards

Responsibility Reinforcement Conditioning Therapy

The Wetness Alarm Alarm Results

 Complete resolution 66%

 16% relapse after discontinuation

 Relapses respond well to retreatment

 Better with overtreatment

Glazener, C. M., J. H. Evans, et al. (2005). "Alarm interventions for nocturnal enuresis in children." The Cochrane database of systematic reviews(2): CD002911.

4. Catheterizable Continent Channels Clean Intermittent Catheterization

 Urethra  Manual Dextrerity  Balance Issues

 Stoma  Mitrofanoff

Mitrofanoff Catheterizable Conduit

The appendix preferred material for a continent cathetrizable conduit. 55

56 10 Years Later

57

58 MACE

MACE Appendiceal Inlay 5. UTI

Pathogenesis of UTI

 Access

 Incubation

 Adhesion Evaluation

 Review Urine Culture and Analysis Report  Elimination Diary & Drinking Habits  US  FR & PVR

Time Amount Wet / Dry Investigations for UTI

 If no Hx of BBD: US

 VCUG only if US abnormal  HN  HU  Bladder

Management

 Correction of Predisposing Factors  Insufficient water intake  Infrequent voiding  Incomplete bladder emptying  Constipation  Poor Hygiene, Fecal soiling  Voiding into vagina  Chemical urethritis 6. VUR

Indications for Surgical Correction of VUR 1990’s

 Breakthrough infections  Non resolution after 4 years of Follow-up  Noncompliance with ABP  New renal scars on therapy AAP Guidelines 2011

 Published literature does not provide evidence supporting the benefit of prophylaxis Rec UTI or renal scarring

 Therefore why diagnose VUR when the imaging findings would not affect the nature of treatment? Swedish Reflux Trial

 Antibiotic prophylaxis and endoscopic treatment decreased the infection rate in:  Children under 2 y  with Grade III-IV VUR Be Selective Renal Scarring

 Outcome scans (at the 2year visit or 3 to 4 months after the child had met treatment failure criteria) showed no significant differences in the incidence of renal scarring

 11.9% in the prophylaxis group and 10.2% in the placebo group (P = 0.55),

 Severe renal scars (4.0% and 2.6%, respectively; P = 0.37

 New renal scars since baseline (8.2% and 8.4% P=0.94) Compliance

 Parents of 467 of the children (76.9%) reported having administered the study medication at least 75% of the time,  Parents of 517 children (85.2%) reported having administered it at least 50% of the time.  Parents of 91 children in the prophylaxis group and of 76 children in the placebo group discontinued the study medication.

Antimicrobial Resistance

 Stool colonization with resistant E. coli was more common in the prophylaxis group than in the placebo group, but the difference was not significant  Among 87 children with a first febrile or symptomatic recurrence with E. coli, the proportion of isolates that were resistant to TMP-SMX was 63% with prophylaxis and 19% with placebo (P<0.001) How does this reconcile with the AAP Guidelines?

1. CAP does not reduce renal scarring or CKD 2. CAP results in a modest reduction in UTIs 3. The likelihood of resistant organisms causing UTI is higher in the group on CAP 4. Do the results with SMX-TMP cross over to other antibiotics?

Bladder and Bowel Dysfunction Outcome of Antibiotic Prophylaxis Discontinuation in Patients With Persistent Vesicoureteral Reflux Initially Presenting With Febrile Urinary Tract Infection: Time to Event Analysis Bruno Leslie, Katherine Moore, Joao L. Pippi Salle, Antoine E. Khoury, Anthony Cook, Luis H.P. Braga, Darius J. Bägli, Armando J. Lorenzo The Journal of Urology - September 2010 (Vol. 184, Issue 3, Pages 1093-1099

I-II

III-V

Outcome of Antibiotic Prophylaxis Discontinuation in Patients With Persistent Vesicoureteral Reflux Initially Presenting With Febrile Urinary Tract Infection: Time to Event Analysis Bruno Leslie, Katherine Moore, Joao L. Pippi Salle, Antoine E. Khoury, Anthony Cook, Luis H.P. Braga, Darius J. Bägli, Armando J. Lorenzo The Journal of Urology - September 2010 (Vol. 184, Issue 3, Pages 1093-1099

No BBD

BBD The Journal of Urology Volume 184, Issue 3 , Pages 1134-1144, September 2010 Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children

Craig A. Peters, Steven J. Skoog, Billy S. Arant Jr., Hillary L. Copp, Jack S. Elder, R. Guy Hudson, Antoine E. Khoury, Armando J. Lorenzo, Hans G. Pohl, Ellen Shapiro, Warren T. Snodgrass, Mireya Diaz

 BBD is associated with more UTIs on CAP

 BBD is associated with less reflux resolution at 24 month

 BBD is associated with reduced success for endoscopic therapy but not open surgery

 BBD is associated with increased incidence of UTI after surgery Predicting The Risk For Breakthrough Urinary Tract Infections In Patients With Primary Vesicoureteral Reflux

Guy Hidas, John Billimek , Alexander Nan, Blake Watts, Maryellen Pribish, Soltani Tandis, Elias Wehbi, Irene McAleer, Gordon McLorie, Sheldon Greenfield, Sherrie H. Kaplan, Antoine E. Khoury

University of California, Children's Hospital of Orange County, Orange, CA, USA

Number of Grade of VUR Presence of Febrile Parenchymal Prenatal UTI changes Or Post UTI Age VUR is aInfant spectrumBladder Sex Vs. Dysfunction Race >5 y Constipation

Prevention of Renal Injury Methods

Retrospective Data Review to Construct Risk Calculator

Prospective Application of Risk Calculator To evaluate accuracy

Prospective Validation of Risk Model

We tested the risk model on a prospective cohort of 56 patients with VUR followed for two years

 Mean probability prediction of BTUTI using the model was 19.5%  21% (12 patients) actually experienced BTUTI  The model also showed good discrimination between positive versus negative BTUTI cases in this prospective sample (AUROC= 0.80). VUR BTUTI Risk Score Calculator http://www.paperact.com/ireflux.html Categorical risk stratification

% of Pop • VUR Grade I-III and BUTI Risk Low Risk No BBD 67% 8% • Circumcised Male

• VUR Grade I-III and BBD Intermediate • Uncircumcised Male 27% 27% • VUR Grade IV-V, Female, Risk Presented as PNH

• VUR Grade IV and V High Risk •and Female 6% 62% • and Presented as a UTI

VUR Score

 Low Risk: Nothing ± Periodic RBUS  Intermediate Risk: CAP + Periodic RBUS  High Risk: early intervention  Females after puberty???? 7. Hematuria

Microscopic Hematuria

 Microscopic hematuria is a common finding in children.  In two large population-based studies, 3-4% of unselected school-age children between 6 to 15 years of age had a positive dipstick for blood in a single urine sample  Drops to 1% or less for two or more positive samples. Among the 1 percent of children with two or more positive urines for hematuria, only one-third have persistent hematuria (positive repeat test after six months)  Routine office screening with urinalysis for urinary abnormalities is no longer recommended.

 The actual time of onset for microscopic hematuria is often unknown

Microscopic Hematuria

 Confirmation of microscopic hematuria after a positive dipstick examination requires a microscopic examination of the urine for the presence of red blood cells and casts. Glomerular VS. Nonglomerular Bleeding

Extraglomerular Glomerular Red, smoky brown, or Color (if macroscopic) Red or pink "Coca‐Cola" Clots May be present Absent Proteinuria Usually absent May be present RBC morphology Normal Dysmorphic RBC casts Absent May be present

Thin Basement Membrane Disease

 Thin basement membrane disease (TBM), also called benign familial hematuria, is an autosomal dominant condition Hypercalciuria

 Defined in children as a urine calcium/creatinine ratio >0.2 (mg/mg) in children older than six years of age,  In studies performed in the United States, the prevalence has ranged from as low as 11 percent in the Northeast to as high as 35 percent in the South.  Association between hypercalciuria and hematuria may be more common in areas where there is a higher prevalence of nephrolithiasis.

Transient hematuria

 Urinary tract infection (dysuria and pyuria)

 Trauma

 Fever

 Exercise-induced hematuria Evaluation

 Hx: UTI, Stone, Water intake, Trauma, Menstruation

 Remember to examine urethral meatus

Recommendation

 Observation of children with asymptomatic microscopic hematuria with normal physical examination.

 Extensive diagnostic evaluation reserved only in children with:  Proteinuria  Hypertension  Gross hematuria Gross Hematuria

40 40 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0

Nephrology Urology

Gross Hematuria

 Terminal Hematuria = Urethral source

 Exercise induced

 AVM

 Ca:Cr ratio >0.2 (mg/mg)

 Diet: Water + citrate + Less NaCl

 Consider an US if persistent

 Cystoscopy rarely indicated 8. Modern Management of the Undescended Testicle

Epidemiology At birth:

 3-4% of full-term male infants

 25-45% of pre-term male infants At 6 and 12 months:

 1% of full-term males

 10% of pre-term male infants 10-25% are bilateral Testicular Ascent

Well documented in the literature Various theories on the etiology:

 Patent processus (found in 25-47% at surgery)

 Spasticity of cremasteric reflex

 Relative cranial migration due to linear growth

Similar abnormalities of germ cell development have been observed

Barthold and Gonzalez; J Urology 2003

Retractile testicle

Can be manipulated into the scrotum and stays there for an undefined period of time

 Most commonly seen at 5 yrs of age

 Hyperactive cremasteric reflex

 Should be monitored annually until puberty

 7-33% “progress” to cryptorchidism Physical examination

 Warm, relaxed environment

 Sweep fingers from internal ring to external ring

 Facilitated by use of lubricant

 Try supine first, then in a seated, cross-legged position

What is the Role of Imaging?

None Ultrasound vs. Physical Exam Tasian and Copp; Pediatrics 2011  Systematic review and meta-analysis

 12 studies (591 testes)

 US has sensitivity of 45% and specificity of 78% Conclusion – US does not reliably localize nonpalpable testes and does not rule out an intraabdominal testis.

No change in surgical management based on ultrasound findings!

Bilateral Non-palpable Testes

 Karyotype and endocrine evaluation particularly when associated with hypospadias

Surgical exploration still required! Kollin, Claude, Hesser, Ulf, Ritz, E Martin and Karpe, Bengt (2006) 'Testicular growth from birth to two years of age, and the effect of orchidopexy at age nine months: A randomized, controlled study', Acta Paediatrica, 95:3, 318 - 324

Testicular Cancer

Pettersson et al; NEJM 2007

 16,983 men underwent orchiopexy between 1964 and 1999

 56 cases of testis cancer (0.3%)

 Orchiopexy < 13yrs of age - RR = 2.23

 Orchiopexy ≥ 13 yrs of age - RR = 5.40 Testicular Cancer

 Educate parents

 Most common cancer among men age 15-35yrs

 Recommend testicular self- exams starting in adolescence

Take home messages

 Imaging is unnecessary

 Normal paternity rates in unilateral cryptorchidism; decreased rates in bilateral

 Ideal age for surgery is 6-12 months

 Testicular self-exams starting in adolescence 9. DSD

Gender Assignment

 4 components of psychosexual development  gender identity  gender role  sexual identity  sexual orientation. Factors Influencing Psychosexual Development

 Exposure to androgens

 Sex chromosomes

 Compliance

 Brain structure

 Social circumstance

 Family dynamics.

Gender Assignment

 3 important factors  Expected gender identity  Sexual function  Fertility potential  Other factors that may be considered include  genital appearance  gonadal malignant potential  need for gonadectomy  surgical options  prenatal androgen exposure  views of the family  cultural practices.  The external masculinization score (EMS) has been used to aid this process. (Ahmed SF, Khwaja O and Hughes IA: The role of a clinical score in the assessment of ambiguous genitalia. BJU Int. 85: 120-4,) 2000.

Influence of Sex Hormones on the Developing Brain

 Prenatal exposure contributes to gender identity  Current recommendation: genetic males be reared as male  micropenis  penile agenesis  46,XY males with PAIS  5-alpha reductase deficiency.  The majority of patients with 46,XX CAH and 46,XY CAIS patients identify as female

 despite exposure to elevated androgen levels during fetal life.

 It is recommended these patients are gender assigned as female

CAH: Prenatal DEX Treatment

 Family History

 Start at 6-7 week of pregnancy

 Females only (7/8 fetuses treated unnecessarily) Cell-free Fetal DNA Testing

 Cell-free fetal DNA testing, a noninvasive prenatal screening of fetal DNA in maternal circulation, can provide early sex identification and genotyping without amniocentesis or chorionic villus sampling, and thus decreases unnecessary prenatal CAH dexamethasone therapy.

Feminizing Genitoplasty

 vaginoplasty

 clitoroplasty

 Labioplasty

 Skin Buccal mucosa graft

Hypospadias Reconstruction 10. Prepuce

Function of the prepuce

 Protection of the glans Infant “Smegma”

 Penile pearls  Penile abscess  Penile cysts  Penile mass  Penile calcifications •Desquamated cells •Helps separation

Infants

Q-tips Irrigation AntisepticsX Phimosis

Physiologic phimosis By 3 years of age, 90% of foreskins are retractable, less than 1% of males have phimosis by 17 years of age.

Early forceful retraction is not recommended

"Iatrogenic" Phimosis Management of Physiologic Phimosis

 Steroid + Gentle retraction 95% success

 Gentle retraction alone 45% success (p<0.001)

Indications for Circumcision

Medical Social Religious • Penile and cervical cancer Hygiene • Sexually transmitted diseases • Phimosis and lessening of the Cosmetic risk of balanitis.