This Month in Pediatric Urology

Article Outline

• The Swedish Reflux Trial in Children: I. Study Design and Study Population Characteristics
• The Swedish Reflux Trial in Children: II. Outcome of Vesicoureteral Reflux
• The Swedish Reflux Trial in Children: III. Pattern of Urinary Tract Infections
• The Swedish Reflux Trial in Children: IV. Renal Damage
• The Swedish Reflux Trial in Children: V. Bladder Dysfunction
• In Vitro Antibacterial Activity of Trimethoprim
• Extravesical Ureteral Reimplantations Performed in an Outpatient Setting
• Copyright

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The Swedish Reflux Trial in Children: I. Study Design and Study Population Characteristics 

The management and outcomes of different management strategies for vesicoureteral reflux (VUR) remain controversial topics in pediatric urology, in part due to the dearth of properly planned prospective, randomized clinical trials in the various subpopulations of children with VUR. Following a Swedish state-of-the-art conference initiated by the late Dr. Jan Winberg in 1994 to develop management guidelines and identify future research projects, a randomized, multicenter study was performed to investigate the 3 treatment alternatives of antibiotic prophylaxis, endoscopic treatment and surveillance without preventive measures. In this first of a 5-part series (page 274) the study design and study population characteristics of the 6-year Swedish Reflux Trial are detailed. The primary aims of the study were to compare the rate of febrile urinary tract infections (UTIs), kidney damage and reflux status after 2 years in all 3 groups. The trial included 23 pediatric centers, of which 22 covered 80% of the Swedish population of 9 million and 1 included the population in Oslo, Norway. Study inclusion criteria were grades III and IV VUR, and patient age 1 to 2 years. Recruitment was more difficult than expected, and enrollment was stopped after 6 years with a total of 128 girls and 75 boys entered into the study. Thus, the total study population for all 5 parts of this series is 203 children.

All patients were evaluated with a baseline ultrasound, voiding cystourethrogram, dimercaptosuccinic acid (DMSA) scan and excretory urogram. The first UTI occurred at a median age of 0.78 years in girls and 0.26 years in boys, bilateral VUR was present in 55% of patients and DMSA scans were abnormal at study entry in 54% of patients. At 2-year followup DMSA scan was performed in all but 2 patients and voiding cystourethrogram was performed in all but 18. A total of 187 patients completed 6 or more of the scheduled 8 followup contacts. The authors conclude that despite difficult recruitment, a substantial number of patients were randomized and overall adherence to the protocol was good.

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The Swedish Reflux Trial in Children: II. Outcome of Vesicoureteral Reflux 

In part 2 of this 5-part series (page 280) reflux status is compared after 2 years of treatment with low dose antibiotic prophylaxis (69 patients), endoscopic subureteral implantation of dextranomer/hyaluronic acid copolymer (66) or surveillance (68). The endoscopic procedure was performed at 6 pediatric surgical centers. Of 82 girls and 51 boys in the surveillance and prophylaxis groups grade III–IV VUR resolved in 16% and 12%, and was downgraded to grade I in 5% and 12%, and grade II in 28% and 24%, respectively. Of the 66 patients in the endoscopic group VUR resolved in 59%, and was grade I in 6%, grade II in 21%, grade 3 in 9% and grade IV in 5% 3 months after 1 or 2 injections. However, grade III or IV VUR recurred 2 years after either prior resolution or downgrading to grade I or II. The authors conclude that although initial results of endoscopic treatment were significantly better than the spontaneous rate of resolution or downgrading of VUR in the prophylaxis and surveillance groups, the frequent recurrence of grade III or IV VUR after 2 years is a concern.

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The Swedish Reflux Trial in Children: III. Pattern of Urinary Tract Infections 

In part 3 of this 5-part series (page 286) the pattern of UTI was compared across the 3 treatment groups. Of the 203 children 194 presented initially after a symptomatic UTI and in 9 UTI was detected on prenatal sonography. Patients were followed clinically for 2 years with regular visits and telephone contacts every 3 months to assess for episodes of fever, intercurrent illnesses, antibiotic consumption and UTIs. UTI was diagnosed when bacteriuria was 100,000 or greater colony forming units in urine obtained by midstream or bag, or any number after suprapubic aspiration. Overall 26% of patients experienced a total of 91 new symptomatic UTIs, of which 16 were nonfebrile. New febrile UTIs occurred in 33% of girls and 9% of boys (p=0.0002). Febrile UTI recurred in 19% of girls in the prophylaxis group, 23% in the endoscopic group and 57% in the surveillance group. The difference in number of recurrences between the treatment groups and the surveillance group was statistically significant, while the difference between the prophylaxis and endoscopic groups was not. The median time to UTI recurrence was significant among the treatment groups in girls (log-rank <0.0001) but not in boys. The association between higher grade VUR and an increased UTI recurrence rate at 2-year followup was significant in girls (p=0.0095) but not in boys. The authors conclude that active treatment (antibiotic prophylaxis and endoscopic therapy) compared to surveillance reduces the recurrence rate of febrile UTI in girls but not in boys older than 1 year.

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The Swedish Reflux Trial in Children: IV. Renal Damage 

In part 4 of this 5-part series (page 292) the development of new renal damage is compared among the 3 treatment groups. DMSA scans were abnormal at study entry in 61% of patients. At followup new damage in previously unscarred renal areas or a decrease in relative function of greater than 3% in a kidney with defects at study entry was seen in 17 girls and 7 boys, including 6% in the prophylaxis group, 12% in the endoscopic group and 18% in the surveillance group. However, these differences were not statistically significant (p=0.11). Deterioration also occurred in 31% of children with and 6% without febrile UTI recurrence (p <0.0001). New scarring developed significantly more often in the surveillance group compared with the prophylaxis group (p=0.0054), whereas the difference between the endoscopic and prophylaxis groups, and between the endoscopic and surveillance groups did not reach statistical significance. The authors conclude that overall the rate of new renal damage is low, although it is significantly higher in girls, particularly in the surveillance (control) group, and there is a strong association between the development of new scars and recurrent febrile UTIs.

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The Swedish Reflux Trial in Children: V. Bladder Dysfunction 

In the final part of this 5-part series (page 298) the prevalence and types of lower urinary tract dysfunction in young children with grades III and IV VUR are discussed. At study entry functional bladder capacity and post-void residual urine were documented in 148 children during a 4-hour observation period. At 2-year followup 161 children were evaluated by a noninvasive residual flow study, including assessment of functional bladder capacity and flow curve patterns, and a voiding questionnaire. At study entry 20% of the patients had high bladder capacity and high residual urine. At 2 years 34% of patients had lower urinary tract dysfunction (LUTD), including isolated overactive bladder in 9%, dysfunctional voiding in 10%, dysfunctional elimination syndrome in 7% and dilated bladder dysfunction in 7%. Febrile UTI recurred in 33% of those with LUTD vs 20% with normal bladder function (p=0.084). VUR improved in 22% of patients with LUTD vs 56% with normal bladder function (p=0.002). Renal damage at entry and followup was more common in the LUTD group than in normal children (p=0.007 and p=0.002, respectively). The authors conclude that approximately a third of young children with grade III or IV VUR have LUTD after being toilet trained, and bladder dysfunction is associated with persistent VUR and increased risk for renal damage. However, LUTD at ages 1 to 2 years does not predict outcome after 2 years.

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In Vitro Antibacterial Activity of Trimethoprim 

One of the most commonly used antibiotics for prophylaxis of VUR in children is the combination of trimethoprim (TMP) and sulfamethoxazole (SMX). However, approximately 3% of patients have allergic reactions to SMX. In a prospective, multi-institutional, in vitro study Nguyen et al (page 305) compared the antibiotic susceptibility of Escherichia coli to TMP with TMP/SMX combination and SMX alone in 1,298 children with culture documented urinary tract infection. In vitro susceptibility and resistance testing of the bacterial isolates to these antibiotics were determined using the standardized disk diffusion method. The in vitro susceptibility was 70% for TMP and TMP/SMX, and 56.9% for SMX alone. Of the isolates 165 were susceptible to TMP but resistant to SMX, 22 were susceptible to TMP but intermediate to SMX and 15 were susceptible to SMX but resistant to TMX. Increased susceptibility of E. coli to TMP and TMP/SMX vs SMX was noted at all 4 institutional sites. The authors conclude that the addition of SMX to TMP does not provide an increase in in vitro antibacterial activity but exposes patients to increased risk of adverse drug reactions. Therefore, the routine use of TMP/SMX combination to treat urinary tract infections needs to be reevaluated clinically and the alternate use of TMP alone needs to be reconsidered.

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Extravesical Ureteral Reimplantations Performed in an Outpatient Setting 

Extravesical ureteral reimplantation has a high success rate for eliminating VUR and is less morbid than other intravesical reimplantation techniques. In a retrospective study Wicher et al (page 311) from Salt Lake City, Utah report their experience with 250 consecutive outpatient extravesical ureteral reimplantations for primary VUR. Parents were counseled in clinic and on the day of surgery regarding the expectation that the child would go home that day. A modified Lich-Gregoir reimplantation was performed and incisional block with 0.25% bupivacaine was given at the end of the procedure. Caudal blocks were not used. Most patients received intravenous ketorolac and ondansetron before leaving the operative suite. Discharge criteria included adequate pain control with an oral analgesic (hydrocodone-acetaminophen), spontaneous voiding and the ability to eat. Various short-term complications occurred in 9 (3.6%) patients and late febrile urinary tract infections occurred in 8 (3.2%). The authors conclude that unilateral extravesical ureteral reimplantation for primary VUR can be performed on an outpatient basis with no significant increase in overall morbidity.