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High Grade Primary Vesicoureteral Reflux in Boys: Long-Term Results of a Prospective Cohort Study
High Grade Primary Vesicoureteral Reflux in Boys: Long-Term Results of a Prospective Cohort Study Basim S. Alsaywid, Hamda Saleh, Aniruddh Deshpande, Robert Howman-Giles and Grahame H. H. Smith* From the Urology (BSA, AD, GHHS) and Nuclear Medicine (HS, RHG) Departments, Children’s Hospital at Westmead and Discipline of Imaging and Paediatrics and Child Health, Sydney Medical School, University of Sydney (RHG), Sydney, New South Wales, Australia
Abbreviations and Acronyms BPD ⫽ baseline perfusion defect CAP ⫽ continuous antibiotic prophylaxis DMSA ⫽ 99mtechnetiumdimercapto-succinic acid NPD ⫽ new permanent defect UTI ⫽ urinary tract infection VCUG ⫽ voiding cystourethrography VUR ⫽ vesicoureteral reflux Study received Children’s Hospital at Westmead ethics committee approval. * Correspondence: Urology Department, Children’s Hospital at Westmead, Crn. Hawkesbury Road and Hainsworth St., Locked Bag 4001, Westmead, New South Wales, 2145, Sydney, Australia (telephone: (02)98453349; FAX: (02) 98453180; e-mail: [email protected]).
Purpose: We evaluated the incidence of new permanent defects in boys with grade 4 or 5 vesicoureteral reflux, identified the risk factors for new permanent defects and reviewed the outcome of different management approaches by assessing the rates of urinary tract infection and new permanent defects. Materials and Methods: This prospective cohort study recruited patients from July 1995 to December 2006. Study inclusion criteria were male gender and grade 4 or 5 primary vesicoureteral reflux. Patients were divided into 2 groups by presentation mode, including group 1—prenatal reflux diagnosis and group 2—reflux diagnosed after investigation for urinary tract infection. All patients underwent initial renal 99mTc-dimercapto-succinic acid scan evaluation. Continuous antibiotic prophylaxis was given in all patients until at least age 2 years. Surgical correction for reflux was done in 28 patients and 76 were circumcised. Followup included renal 99mTc-dimercapto-succinic acid scan with renal ultrasound at age 12 months with repeat 99mTc-dimercapto-succinic acid scan at ages 2 and 4 years. Results: Included in our study were 151 patients (206 high grade refluxing renal units) with a median age at diagnosis of 1.9 months (range 1 day to 8.8 years). Median age at first followup was 14 months (range 3 months to 3 years) and at next followup it was 39 months (range 10 months to 11.3 years). There were 52 boys (34%) in group 1 and 99 (66%) in group 2. Baseline perfusion defects on initial renal 99mTc-dimercapto-succinic acid scan were identified in 41 of 52 boys (78.8%) in group 1 and in 74 of 99 (74.7%) in group 2. During followup new permanent defects developed in 8 of 52 boys (15%) in group 1 and in 10 of 99 (10%) in group 2. In 18 patients a total of 20 renal units showed new permanent defects, including 13 in kidneys with baseline perfusion defects and 7 in previously normal kidneys (p ⬎0.9). In groups 1 and 2 combined infection developed before and after circumcision in 62 of 137 (45.2%) and 5 of 74 cases (6.7%), respectively (p ⬍0.001). New permanent defects were seen in 4 of 76 circumcised (5.2%) and in 14 of 137 uncircumcised boys (10.2%) (p ⬎0.3). Conclusions: Baseline perfusion defects were seen on 99mTc-dimercapto-succinic acid scan at presentation in 115 of our 151 patients (76%) independent of presentation mode. New permanent defects developed in abnormal and previously normal kidneys, and were associated with urinary tract infection. Being circumcised was associated with fewer urinary tract infections and a lower incidence of observed new permanent defects (5.2% vs 10.2%). Key Words: kidney, vesico-ureteral reflux, circumcision, urinary tract infections, male
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0022-5347/10/1844-1598/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
Vol. 184, 1598-1603, October 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.04.021
HIGH GRADE PRIMARY VESICOURETERAL REFLUX IN BOYS
THE main aim in treating VUR is to prevent progressive renal injury and UTI. The best treatment to achieve this remains unclear. The damaging effect of sterile VUR is controversial. Observational evidence suggests that new renal scarring is associated with recurrent UTIs. Hence, preventing UTI may serve to prevent hospitalization for infection and prevent progressive renal scarring. The Birmingham VUR1 and the international VUR2,3 trials failed to show any benefit for surgical correction of VUR over that of prophylactic antibiotics when the outcome measure was new renal injury. More recently the benefits of prophylactic antibiotics have been called into question.4 – 6 Evidence shows circumcision decreases the risk of febrile UTI between 5 and 10 times in boys.7 Thus, circumcision may be more effective than ureteral reimplantation to prevent renal scarring in boys. Males with grade 4 or 5 VUR have the highest rate of congenital renal DMSA abnormalities and the highest rate of breakthrough UTIs. This makes them prone to new scar formation and further renal function deterioration. Unfortunately they are also at highest risk for complications after surgical correction of VUR.8 –10 For these reasons VUR treatment in our cohort study was conservative but patients were aggressively investigated to monitor progress. Antibiotics were continued for the first 2 years of life since this is the time when kidneys are most prone to new injury.1,11 Our study aims were to 1) evaluate the BPD incidence at presentation, 2) evaluate the NPD incidence, 3) identify risk factors associated with NPD and 4) review the outcome of different management approaches, particularly the rates of febrile UTI and NPD.
MATERIALS AND METHODS Approval for the study was granted by the Children’s Hospital at Westmead ethics committee. In this longitudinal, prospective cohort study male patients with grade 4 or 5 (high grade) primary VUR were recruited from July 1995 to December 2006 by 1 consultant surgeon (GHHS). VUR was diagnosed by voiding cystourethrogram and VUR was graded according to International Reflux Study Committee guidelines.12 Patients with VUR and neurogenic bladder, exstrophy complex and obstructive uropathy, including ureterocele, posterior urethral valves, ipsilateral ureterovesical junction obstruction or ipsilateral ureteropelvic junction obstruction, were excluded from analysis. Patients were divided into 2 main groups by presentation mode. Boys in group 1 presented with prenatal hydronephrosis and were diagnosed with high grade VUR during the postnatal followup investigation. In group 2 patients were diagnosed with high grade VUR after UTI investigation. All patients were maintained on CAP until age 2 years. If a patient presented after age 2 years, CAP was continued for 6 months. All patients underwent initial renal scan with DMSA. Followup investigations included DMSA
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scan and renal ultrasound at ages 12 months, and 2 and 4 years (fig. 1). Renal parenchymal abnormality was evaluated by DMSA scan according to our protocol.13 All DMSA studies were interpreted by 1 senior nuclear medicine specialist (HS) blinded to the original scan reports. In case of discrepancy between the original report and our nuclear medicine specialist report the studies were reviewed by another senior nuclear medicine specialist (RHG) for a final conclusion. Renal abnormality was defined as a kidney with perfusion defects and/or a small kidney with less than 35% function. Renal defects were also graded by the modified Goldraich classification for reflux nephropathy.13,14 The Goldraich classification includes 4 grades, including type 1—no more than 2 cortical defects, type 2—more than 2 with but remnant areas of normal renal parenchyma, type 3— generalized damage to the whole kidney, ie a diffuse decrease in DMSA uptake or whole kidney contraction with or without focal defects, and type 4 —an end stage, shrunken kidney with little or no DMSA uptake, ie less than 10% of overall renal function. NPD on DMSA scan was defined as a defect that appeared during followup and persisted on subsequent scan.14 Voiding dysfunction was diagnosed after the toilet training age using International Children’s Continence Society guidelines.15 Data collection and analysis were done using SPSS®, version 17. We used the nonparametric chi-square test with p ⬍0.05 considered statistically significant. All p values were 2 sided.
RESULTS Demographics Median age at presentation in the 151 patients (206 renal units) was 1.9 months (range 1 day to 8.8 years). Median followup was 39 months (range 10 months to 11.3 years). Of the 151 boys 101 (67%) had bilateral reflux but only 55 (36.4%) had high grade bilateral VUR. Of the 206 renal units with high grade VUR 101 (49%) had right and 105 (51%) had left VUR.
Figure 1. DMSA study planar images. A, normal. B, in 5-year-old boy with prenatal hydronephrosis, bilateral grade 5 VUR and no documented UTI followup scan shows bilateral cortical defects (arrows) and thinning, unchanged from baseline study at age 2 months. L, left. POST, posterior. R, right. RAO, right anterior oblique. LAO, left anterior oblique.
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Table 1. Patient demographics and presentation Group 1 No. pts (%) No. renal units/total No. (%): Grade 4 Grade 5 No. pts laterality (%): Unilat Bilat ⫹ low grade VUR Bilat ⫹ high grade VUR Median age at presentation (range) Median followup (range) No. pts voiding dysfunction (%) No. circumcision (%): Neonatal Overall Median age at circumcision (mos) No. pts surgery (%) Median age at surgery
52 78/206 37/78 41/78
Group 2 (34) (38) (47) (53)
99 128/206 80/128 48/128
Overall (66) (62) (62) (38)
151 206 117/206 89/206
(100) (100) (57) (43)
18 (35) 8 (15) 26 (50) 14.5 Days (1 day–12.6 mos) 42 Mos (12 mos–10 yrs) 8 (15)
32 (32) 38 (38) 29 (29) 5.6 Mos (4 days–8.8 yrs) 37 Mos (10 mos–11.3 yrs) 11 (11)
50 (33) 46 (31) 55 (36) 1.9 Mos (1 day–8.8 yrs) 39 Mos (10 mos–11.3 yrs) 19 (13)
11 23 2 8 26 Mos
3 53 11 20 34 Mos
14 76 8.5 28 30 Mos
(22) (45) (15) (8 mos–4 yrs)
Grade 4 and 5 VUR was found in 117 (56.8%) and 89 renal units (43.2%), respectively. A total of 52 patients (34%) were diagnosed after investigation for prenatal hydronephrosis (group 1) and 99 (66%) were diagnosed with high grade VUR after febrile UTI (group 2). Median followup in the 2 groups was similar. Two patients in group 1 and 5 in group 2 were clearly noncompliant with antibiotic intake. A total of 19 patients (12.6%) had voiding dysfunction. NPD developed in 18 patients (11.9%). While on antibiotics, breakthrough UTI developed in 63 patients (41.7%). The mean number of breakthrough febrile UTIs in the study was 2.56 (range 1 to 8). Escherichia coli was the most common organism isolated (54.8% of cases), followed by Enterococcus faecalis (14.4%), Enterobacter cloacae and Klebsiella (7.7%). Circumcision was done in 76 patients, including 14 in the neonatal period and 2 (3%) who later underwent antireflux surgery. Median age at circumcision was 8.5 months (range 1 month to 5.4 years). Median followup after circumcision was 30.5 months (range 9 months to 5.02 years). In the uncircumcised group there were 75 patients, of whom 26 (35%) underwent antireflux surgery and 47 were treated with antibiotics alone. In the 2 groups 28 patients underwent antireflux surgery with a median age at surgery of 30 months (range 8 months to 7.6 years). Median postoperative followup was 15 months (range 8 to 29 months). Table 1 lists patient demographics. Renal Parenchymal Abnormality Rate Abnormal findings on initial DMSA scan (BPD and/or a small kidney) were noted in 125 patients (82.8%). BPD according to the Goldraich classification13,14 was identified in 115 patients (76.2%). Table 2 lists findings by patient. Abnormal findings were identified on DMSA scan in 145 renal units (70.4%). Grade 5 VUR had a higher
(3) (54) (20) (11 mos–7.6 yrs)
(9) (50) (19) (8 mos–7.6 yrs)
rate of DMSA abnormality than grade 4 VUR (74 of 89 cases or 83% vs 71 of 117 or 60.7%, p ⬍0.001). BPD was identified in 133 renal units (64.6%). BPD was noted in 69 of 89 patients (77.5%) with grade 5 VUR vs 64 of 117 (55%) with grade 4 VUR (p ⬍0.001). When combining groups 1 and 2, BPD was observed in the upper, mid and lower pole in 33%, 27% and 40% of cases, respectively. Table 3 lists findings by renal unit. Table 4 shows the BPD rate by different grades of the modified Goldraich classification13,14 and the rate of small kidneys with dysplasia and hypoplasia. The NPD incidence was 11.9% (18 of 151 boys) for a rate of 3.67 NPDs/100 patients per year. Median patient age at NPD was 2.2 years (range 10 months to 4.8 years) (fig. 2). Febrile UTI was documented in 13 patients (72.2%) before NPD formation. Eight of 52 group 1 patients (15%) and 10 of 99 in group 2 (10%) had NPDs (p ⫽ 0.4). NPDs developed in 8 of 19 patients (42%) with voiding dysfunction. The NPD incidence was significantly higher in these cases (OR 8.8, 95% CI 2.92–26.92, chi-square 18.8, 1 df, p ⬍0.001). After circumcision 4 of 76 children (5.2%) had NPDs while NPDs were noted in 14 of 137 (10.2%) who were not offered circumcision or before circumcision (p ⫽ 0.3). Only 1 of the 14 children who underwent circumTable 2. BPD and small kidney initial DMSA scan findings by patient presentation
Overall Renal abnormality Unilat/total abnormality Bilat/total abnormality BPD Unilat/BPD Bilat/BPD
No. Group 1/Total No. (%)
No. Group 2/Total No. (%)
No. Overall/Total No. (%)
52/151 (34) 43/52 (83) 33/43 (77) 10/43 (23) 41/52 (79) 32/41 (78) 9/41 (22)
99/151 (66) 82/99 (83) 65/82 (79) 17/82 (21) 74/99 (75) 59/74 (80) 15/74 (20)
151 (100) 125/151 (83) 98/125 (78) 27/125 (22) 115/151 (76) 91/115 (79) 24/115 (21)
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Table 3. Initial BPD and small kidney findings on initial DMSA scan by renal unit presentation
Renal abnormality (BPD ⫹/or small kidney): Grade 4 Grade 5 Chi-square p Value Overall BPD: Grade 4 Grade 5 Chi-square p Value
No. Group 1/Total No. (%)
No. Group 2/Total No. (%)
No. Overall/Total No. (%)
52/78 (66.7)
93/128 (72.6)
145/206 (70.4)
19/37 33/41 6.176 0.012 49/78 18/37 31/41 4.954 0.026
52/80 (65) 41/48 (85) 5.309 0.02 84/128 (65.6) 46/80 (58) 38/48 (79) 5.319 0.02
71/117 (61) 74/89 (83) 12.236 ⬍0.001 133/206 (64.6) 64/117 (55) 69/89 (78) 10.537 0.0012
(51) (81)
(63) (49) (76)
cision in the neonatal period had a NPD. Three patients in whom NPDs developed after circumcision also had underlying voiding dysfunction but no documented febrile UTI. NPD developed in 20 renal units (18 patients). Of 133 renal units with BPD 13 (9.8%) had a NPD while NPD developed in 7 of 73 previously normal renal units (9.6%) (p ⬎0.9). Intervention Efficacy for Preventing Breakthrough UTI The incidence of breakthrough UTIs was highest in patients maintained on antibiotics only (table 5). The incidence appeared to be lowest in children who underwent circumcision, although followups were dissimilar.
No. Kidneys/Total No. (%) Group 1
Group 2
Overall
49/78 (63) 3 13
84/128 (66) 23 14
133/206 (65) 26 27
Totals 2/4 2/5
16 3 5
(33)
37 2 5
(44)
53 5 10
(40)
Totals 3/4 3/5
8 8 7
(16)
7 20 12
(8)
15 28 19
(11)
Totals 4/4 4/5
15 4 6
(31)
32 1 7
(38)
47 5 13
(35)
8 (10) 59/128 (46.1) 50 (85) 9 (15) 34 25
18 89 77 12 49 40
(14) (43.2) (87) (13)
Totals Small (hypoplasia ⫹ dysplasia): BPD No BPD Grade 4 VUR Grade 5 VUR
10 (20) 30/78 (38.5) 27 (90) 3 (10) 15 15
Antireflux Surgery Group Surgical treatment for VUR was done in 28 patients, 26 were uncircumcised and 2 underwent surgery after circumcision. Bilateral ureteral reimplantation was done in 19 patients, unilateral reimplantation was done in 5, unilateral reimplantation with contralateral nephrectomy was done in 3 and nephrectomy was done in 1 for a refluxing, nonfunctioning kidney. Five patients (17.9%) had a febrile UTI postoperatively. Two patients had more than 2 febrile UTIs and in 1 end stage renal disease developed. Delayed excretion on postoperative diuretic renal scan was documented in 3 patients (10.7%) (table 6). Two patients (7%) with failure to empty the bladder were treated with clean intermittent catheterization.
DISCUSSION
Table 4. BPD Goldraich classification by renal unit presentation
BPD (Goldraich/VUR grade): 1/4 1/5
Figure 2. Age at new scar formation in boys with high grade VUR.
Our study population represents a highly select group of patients who were considered at high risk. Although prenatal ultrasound is a common practice in Australia, only a third of our patients were diagnosed after investigation for prenatal hydronephrosis. The incidence of renal abnormalities (83%) or BPD (76%) was significantly high compared to most published data.16 –19 This may be explained by the inclusion of only grades 4 and 5 VUR in male patients. Renal parenchymal damage can generally be classified as congenital or acquired with UTI a major risk factor for scar pathogenesis.20,21 Many reports acknowledge the relationship between VUR and congenital defects (hypoplasia and dysplasia) but the high incidence of renal defects is mainly attributable to febrile UTI.21 In our study the BPD rate in the prenatal group was not different from that in patients who presented after UTI. This suggests that the etiology of renal defects is more likely congenital than infectious and the big bang theory is wrong but even the group that performed that study agreed that it is wrong.22,23 Also, screening patients
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Table 5. Breakthrough febrile UTIs by treatment group Antibiotics Only No. pts/No. UTI (%) Median followup (range) OR (95% CI) Chi-square p Value
137/62 (45.2) 38 Mos (10 mos–11 yrs)
with prenatal hydronephrosis by voiding cystourethrogram to identify those with VUR does not seem to prevent renal injury. The same renal injury rate is seen when waiting until the first UTI develops in these boys and then diagnosing VUR. Few studies address the incidence of new DMSA defects in infants with high grade VUR.19,24,25 Overall 18 patients (11.9%, 20 renal units or 9.7%) showed NPD. In 13 patients (72%) febrile UTI preceded defect formation, while 5 had normal urine cultures during followup. Our data suggest another major factor in NPD formation and renal function deterioration. Voiding dysfunction was an important risk factor for NPD in males with high grade VUR. NPD developed in 8 of 19 patients (44%) in this subgroup, significantly more than in the nonvoiding dysfunction group (10 of 132 or 7.6%). Four patients in the subgroup had no documented febrile UTI during followup. This raises the possibility of scarring due to high pressure sterile reflux, similar to that in patients with neurogenic bladder. BPD presence or absence on initial DMSA scan was not related to the risk of NPD. In fact, it was almost identical in the 2 groups, which challenges the concept that abnormal kidneys are at a higher risk for NPD. In the literature there is overwhelming evidence questioning the effectiveness of CAP for preventing febrile UTI.5 In our study CAP failed to prevent a large number of breakthrough UTIs. On the other hand, circumcision seemed to decrease the UTI risk in this group, although separating the effect of circumcision from the effect of prophylactic antibiotics and increasing age made analysis difficult. That is, most UTIs developed in the first year of life and in group 2 circumcision was done in older children. Patients were then older when they were followed and less likely to have a further UTI based on age.
After Circumcision 74/5 (6.7) 30 Mos (9 mos–5 yrs) 0.995 (0.03–0.24) 32.14, 1 df ⬍0.001
After Antireflux Surgery 28/5 (17.8) 15 Mos (8–29) 0.26 (0.09–0.72) 6.145, 1 df ⬍0.001
When deciding on treatment, the risks and harm of treatment must be balanced against the benefits. Circumcision is a relatively simple, inexpensive therapy that seems to be effective for preventing UTI. In contrast, cystoscopy with Deflux® injection is quite expensive with a 51% to 63% high grade VUR resolution rate postoperatively26 and the evidence that this decreases UTI is no better than the evidence that circumcision decreases UTI. Prophylaxis is also considerably less expensive but it does not seem to prevent UTI in many patients. Surgical correction for VUR with open ureteral reimplantation is the most expensive treatment but also the most effective treatment for resolving VUR. Unfortunately the complication rate of open reimplantation is relatively high in this patient group, approaching 10%. The reason for this is not clear8,9 but may be related to preexisting or subsequent abnormal bladder function. The international VUR study showed that obstruction after surgery tends to lead to renal scarring on IVP.2 Thus, this group is at high risk for renal scarring.
CONCLUSIONS Renal parenchymal damage was common in this patient cohort at 76%. The rate of DMSA defects was independent of presentation mode. The new renal defect formation rate was 11.9%. The presence or absence of renal defects on initial DMSA scan had no impact on the development of new defects during followup. Breakthrough febrile UTIs and voiding dysfunction were the main risk factors associated with new scars. Circumcision significantly decreased the incidence of breakthrough UTI and was associated with a lower rate of observed new defects.
Table 6. Patients with bilateral reimplantation and delayed excretion postoperatively
Age at surgery (mos) Complication side Intervention Outcome Voiding dysfunction
Pt 1
Pt 2
Pt 3
24 Rt Neg Whitaker test, noncompliant on clean intermittent catheterization, vesicostomy Stable Yes
22 Lt Clean intermittent catheterization
48 Bilat Unknown secondary ureteropelvic junction, infrequent voiding Improved at 1 yr No
Renal failure Yes
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REFERENCES 1. Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux in children: five years’ observation. Birmingham Reflux Study Group. Br Med J (Clin Res Ed) 1987; 295: 237. 2. Weiss R, Duckett J and Spitzer A: Results of a randomized clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (United States). The International Reflux Study in Children. J Urol 1992; 148: 1667. 3. Hodson E, Wheeler D, Vimalchandra D et al: Intervention for primary vesicoureteric reflux. Cochrane Database Syst Rev 2007; 3: CD001532. 4. Garin E, Olavarria F, Garcia Nieto V et al: Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006; 117: 626. 5. Conway P, Cnaan A, Zaoutis T et al: Recurrent urinary tract infections in children: risk factors and association with prophylactic antimicrobials. JAMA 2007; 298: 179. 6. Williams GJ, Wei L, Lee A et al: Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst Rev 2006; 3: CD001534. 7. Singh-Grewal D, Macdessi J and Craig J: Circumcision for the prevention of urinary tract infection in boys: a systematic review of randomised trials and observational studies. Arch Dis Child 2005; 90: 853. 8. Siegelbaum MH and Rabinovitch HH: Delayed spontaneous resolution of high grade vesi-
coureteral reflux after reimplantation. J Urol 1987; 138: 1205. 9. Upadhayay J, Shekarriz B and Fleming P: Ureteral reimplantation in infancy: evaluation of long-term voiding function. J Urol 1999; 162: 1209. 10. Jodal U, Koskimies O, Hanson E et al: Infection pattern in children with vesicoureteral reflux randomly allocated to operation or long-term antibacterial prophylaxis. The International Reflux Study in Children. J Urol 1992; 148: 1650. 11. Risdon R: The small scarred kidney in childhood. Pediatr Nephrol 1993; 7: 361. 12. Report of the International Reflux Study Committee I: medical versus surgical treatment of primary vesicoureteral reflux—a prospective international reflux study in children. J Urol 1981; 125: 277. 13. Craig JC, Irwig L, Ford M et al: Reliability of DMSA for the diagnosis of renal parenchymal abnormality in children. Eur J Nucl Med 2000; 27: 1610. 14. Goldraich NP and Goldraich IH: Update on dimercaptosuccinic acid renal scanning in children with urinary tract infection. Pediatr Nephrol 1995; 9: 221. 15. Neveus T, von Gontard A, Hoebeke P et al: The standardization of terminology of lower urinary tract function in children and adolescents: report from the Standardisation Committee of the International Children’s Continence Society. J Urol 2006; 176: 314. 16. Hideo N, Hidehiro K, Ryuichiro K et al: Clinical characteristics of primary vesicoureteral reflux in infants: multicenter retrospective study in Japan. J Urol 2003; 169: 309.
17. Caione P, Ciofetta G, Morano S et al: Renal damage in vesico-ureteric reflux. BJU Int 2004; 93: 591. 18. Lama G, Russo M, De Rosa E et al: Primary vesicoureteric reflux and renal damage in first year of life. Pediatr Nephrol 2000; 15: 205. 19. Sjöström S, Jodal U, Sixt R et al: Longitudinal development of renal damage and renal function in infants with high grade vesicoureteral reflux. J Urol 2009; 181: 2277. 20. Goonasekera C and Dillon M: Hypertension in reflux nephropathy. BJU Int 1999; 83: 1. 21. Mohanan N, Colhoun E and Puri P: Renal parenchymal damage in intermediate and high grade infantile vesicoureteral reflux. J Urol 2008; 180: 1635. 22. Ransley PG: Vesicoureteric reflux: continuing surgical dilemma. Urology 1978; 12: 246. 23. Arnold AJ, Sunderland D, Rickwood AM et al: Bacterial factors in the formation of renal scars. An experimental study on the role of Escherichia coli P-fimbriation and hydrophobicity. Br J Urol 1993; 72: 549. 24. Chen J, Pugach J, West D et al: Infant vesicoureteral reflux: a comparison between patients presenting with a prenatal diagnosis and those presenting with a urinary tract infection. Urology 2003; 61: 442. 25. Ylinen E, Ala-Houhala M and Wikstrom S: Risk of renal scarring in vesicoureteral reflux detected either antenatally or during the neonatal period. Urology 2003; 61: 1238. 26. Elder JS, Diaz M, Caldamone AA et al: Endoscopic therapy for vesicoureteral reflux: a metaanalysis. I. Reflux resolution and urinary tract infection. J Urol 2006; 175: 716.
EDITORIAL COMMENT The paradigm for VUR treatment is changing. These authors indicate and substantiate that the most significant factors associated with new perfusion defects in boys with high grade VUR are the lack of breakthrough UTI, which directly correlates with circumcised status, and the presence or absence of voiding dysfunction. They question the effectiveness of antibiotic prophylaxis alone to prevent breakthrough UTI in boys with high grade VUR. Current antibiotic prophylaxis recommendations for VUR treatment in boys younger than 1 year is difficult to determine, given the lack of data on the prevention of acute pyelonephritis. Is the main problem with VUR the morbidity associated with an
increased risk of acute pyelonephritis or the potential acquisition of renal scarring, which in some cases has questionable significance? It may be simplistic to think that newborn circumcision and not antibiotics or surgical intervention may be the indicated treatment to prevent acute pyelonephritis and new perfusion defects in boys with high grade VUR. R. Guy Hudson Pediatric Urology Clinic Medical and Surgical Director Swedish Pediatric Specialty Care Seattle, Washington
Abbreviations and Acronyms BPD ⫽ baseline perfusion defect CAP ⫽ continuous antibiotic prophylaxis DMSA ⫽ 99mtechnetiumdimercapto-succinic acid NPD ⫽ new permanent defect UTI ⫽ urinary tract infection VCUG ⫽ voiding cystourethrography VUR ⫽ vesicoureteral reflux Study received Children’s Hospital at Westmead ethics committee approval. * Correspondence: Urology Department, Children’s Hospital at Westmead, Crn. Hawkesbury Road and Hainsworth St., Locked Bag 4001, Westmead, New South Wales, 2145, Sydney, Australia (telephone: (02)98453349; FAX: (02) 98453180; e-mail: [email protected]).
Purpose: We evaluated the incidence of new permanent defects in boys with grade 4 or 5 vesicoureteral reflux, identified the risk factors for new permanent defects and reviewed the outcome of different management approaches by assessing the rates of urinary tract infection and new permanent defects. Materials and Methods: This prospective cohort study recruited patients from July 1995 to December 2006. Study inclusion criteria were male gender and grade 4 or 5 primary vesicoureteral reflux. Patients were divided into 2 groups by presentation mode, including group 1—prenatal reflux diagnosis and group 2—reflux diagnosed after investigation for urinary tract infection. All patients underwent initial renal 99mTc-dimercapto-succinic acid scan evaluation. Continuous antibiotic prophylaxis was given in all patients until at least age 2 years. Surgical correction for reflux was done in 28 patients and 76 were circumcised. Followup included renal 99mTc-dimercapto-succinic acid scan with renal ultrasound at age 12 months with repeat 99mTc-dimercapto-succinic acid scan at ages 2 and 4 years. Results: Included in our study were 151 patients (206 high grade refluxing renal units) with a median age at diagnosis of 1.9 months (range 1 day to 8.8 years). Median age at first followup was 14 months (range 3 months to 3 years) and at next followup it was 39 months (range 10 months to 11.3 years). There were 52 boys (34%) in group 1 and 99 (66%) in group 2. Baseline perfusion defects on initial renal 99mTc-dimercapto-succinic acid scan were identified in 41 of 52 boys (78.8%) in group 1 and in 74 of 99 (74.7%) in group 2. During followup new permanent defects developed in 8 of 52 boys (15%) in group 1 and in 10 of 99 (10%) in group 2. In 18 patients a total of 20 renal units showed new permanent defects, including 13 in kidneys with baseline perfusion defects and 7 in previously normal kidneys (p ⬎0.9). In groups 1 and 2 combined infection developed before and after circumcision in 62 of 137 (45.2%) and 5 of 74 cases (6.7%), respectively (p ⬍0.001). New permanent defects were seen in 4 of 76 circumcised (5.2%) and in 14 of 137 uncircumcised boys (10.2%) (p ⬎0.3). Conclusions: Baseline perfusion defects were seen on 99mTc-dimercapto-succinic acid scan at presentation in 115 of our 151 patients (76%) independent of presentation mode. New permanent defects developed in abnormal and previously normal kidneys, and were associated with urinary tract infection. Being circumcised was associated with fewer urinary tract infections and a lower incidence of observed new permanent defects (5.2% vs 10.2%). Key Words: kidney, vesico-ureteral reflux, circumcision, urinary tract infections, male
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0022-5347/10/1844-1598/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
Vol. 184, 1598-1603, October 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.04.021
HIGH GRADE PRIMARY VESICOURETERAL REFLUX IN BOYS
THE main aim in treating VUR is to prevent progressive renal injury and UTI. The best treatment to achieve this remains unclear. The damaging effect of sterile VUR is controversial. Observational evidence suggests that new renal scarring is associated with recurrent UTIs. Hence, preventing UTI may serve to prevent hospitalization for infection and prevent progressive renal scarring. The Birmingham VUR1 and the international VUR2,3 trials failed to show any benefit for surgical correction of VUR over that of prophylactic antibiotics when the outcome measure was new renal injury. More recently the benefits of prophylactic antibiotics have been called into question.4 – 6 Evidence shows circumcision decreases the risk of febrile UTI between 5 and 10 times in boys.7 Thus, circumcision may be more effective than ureteral reimplantation to prevent renal scarring in boys. Males with grade 4 or 5 VUR have the highest rate of congenital renal DMSA abnormalities and the highest rate of breakthrough UTIs. This makes them prone to new scar formation and further renal function deterioration. Unfortunately they are also at highest risk for complications after surgical correction of VUR.8 –10 For these reasons VUR treatment in our cohort study was conservative but patients were aggressively investigated to monitor progress. Antibiotics were continued for the first 2 years of life since this is the time when kidneys are most prone to new injury.1,11 Our study aims were to 1) evaluate the BPD incidence at presentation, 2) evaluate the NPD incidence, 3) identify risk factors associated with NPD and 4) review the outcome of different management approaches, particularly the rates of febrile UTI and NPD.
MATERIALS AND METHODS Approval for the study was granted by the Children’s Hospital at Westmead ethics committee. In this longitudinal, prospective cohort study male patients with grade 4 or 5 (high grade) primary VUR were recruited from July 1995 to December 2006 by 1 consultant surgeon (GHHS). VUR was diagnosed by voiding cystourethrogram and VUR was graded according to International Reflux Study Committee guidelines.12 Patients with VUR and neurogenic bladder, exstrophy complex and obstructive uropathy, including ureterocele, posterior urethral valves, ipsilateral ureterovesical junction obstruction or ipsilateral ureteropelvic junction obstruction, were excluded from analysis. Patients were divided into 2 main groups by presentation mode. Boys in group 1 presented with prenatal hydronephrosis and were diagnosed with high grade VUR during the postnatal followup investigation. In group 2 patients were diagnosed with high grade VUR after UTI investigation. All patients were maintained on CAP until age 2 years. If a patient presented after age 2 years, CAP was continued for 6 months. All patients underwent initial renal scan with DMSA. Followup investigations included DMSA
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scan and renal ultrasound at ages 12 months, and 2 and 4 years (fig. 1). Renal parenchymal abnormality was evaluated by DMSA scan according to our protocol.13 All DMSA studies were interpreted by 1 senior nuclear medicine specialist (HS) blinded to the original scan reports. In case of discrepancy between the original report and our nuclear medicine specialist report the studies were reviewed by another senior nuclear medicine specialist (RHG) for a final conclusion. Renal abnormality was defined as a kidney with perfusion defects and/or a small kidney with less than 35% function. Renal defects were also graded by the modified Goldraich classification for reflux nephropathy.13,14 The Goldraich classification includes 4 grades, including type 1—no more than 2 cortical defects, type 2—more than 2 with but remnant areas of normal renal parenchyma, type 3— generalized damage to the whole kidney, ie a diffuse decrease in DMSA uptake or whole kidney contraction with or without focal defects, and type 4 —an end stage, shrunken kidney with little or no DMSA uptake, ie less than 10% of overall renal function. NPD on DMSA scan was defined as a defect that appeared during followup and persisted on subsequent scan.14 Voiding dysfunction was diagnosed after the toilet training age using International Children’s Continence Society guidelines.15 Data collection and analysis were done using SPSS®, version 17. We used the nonparametric chi-square test with p ⬍0.05 considered statistically significant. All p values were 2 sided.
RESULTS Demographics Median age at presentation in the 151 patients (206 renal units) was 1.9 months (range 1 day to 8.8 years). Median followup was 39 months (range 10 months to 11.3 years). Of the 151 boys 101 (67%) had bilateral reflux but only 55 (36.4%) had high grade bilateral VUR. Of the 206 renal units with high grade VUR 101 (49%) had right and 105 (51%) had left VUR.
Figure 1. DMSA study planar images. A, normal. B, in 5-year-old boy with prenatal hydronephrosis, bilateral grade 5 VUR and no documented UTI followup scan shows bilateral cortical defects (arrows) and thinning, unchanged from baseline study at age 2 months. L, left. POST, posterior. R, right. RAO, right anterior oblique. LAO, left anterior oblique.
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HIGH GRADE PRIMARY VESICOURETERAL REFLUX IN BOYS
Table 1. Patient demographics and presentation Group 1 No. pts (%) No. renal units/total No. (%): Grade 4 Grade 5 No. pts laterality (%): Unilat Bilat ⫹ low grade VUR Bilat ⫹ high grade VUR Median age at presentation (range) Median followup (range) No. pts voiding dysfunction (%) No. circumcision (%): Neonatal Overall Median age at circumcision (mos) No. pts surgery (%) Median age at surgery
52 78/206 37/78 41/78
Group 2 (34) (38) (47) (53)
99 128/206 80/128 48/128
Overall (66) (62) (62) (38)
151 206 117/206 89/206
(100) (100) (57) (43)
18 (35) 8 (15) 26 (50) 14.5 Days (1 day–12.6 mos) 42 Mos (12 mos–10 yrs) 8 (15)
32 (32) 38 (38) 29 (29) 5.6 Mos (4 days–8.8 yrs) 37 Mos (10 mos–11.3 yrs) 11 (11)
50 (33) 46 (31) 55 (36) 1.9 Mos (1 day–8.8 yrs) 39 Mos (10 mos–11.3 yrs) 19 (13)
11 23 2 8 26 Mos
3 53 11 20 34 Mos
14 76 8.5 28 30 Mos
(22) (45) (15) (8 mos–4 yrs)
Grade 4 and 5 VUR was found in 117 (56.8%) and 89 renal units (43.2%), respectively. A total of 52 patients (34%) were diagnosed after investigation for prenatal hydronephrosis (group 1) and 99 (66%) were diagnosed with high grade VUR after febrile UTI (group 2). Median followup in the 2 groups was similar. Two patients in group 1 and 5 in group 2 were clearly noncompliant with antibiotic intake. A total of 19 patients (12.6%) had voiding dysfunction. NPD developed in 18 patients (11.9%). While on antibiotics, breakthrough UTI developed in 63 patients (41.7%). The mean number of breakthrough febrile UTIs in the study was 2.56 (range 1 to 8). Escherichia coli was the most common organism isolated (54.8% of cases), followed by Enterococcus faecalis (14.4%), Enterobacter cloacae and Klebsiella (7.7%). Circumcision was done in 76 patients, including 14 in the neonatal period and 2 (3%) who later underwent antireflux surgery. Median age at circumcision was 8.5 months (range 1 month to 5.4 years). Median followup after circumcision was 30.5 months (range 9 months to 5.02 years). In the uncircumcised group there were 75 patients, of whom 26 (35%) underwent antireflux surgery and 47 were treated with antibiotics alone. In the 2 groups 28 patients underwent antireflux surgery with a median age at surgery of 30 months (range 8 months to 7.6 years). Median postoperative followup was 15 months (range 8 to 29 months). Table 1 lists patient demographics. Renal Parenchymal Abnormality Rate Abnormal findings on initial DMSA scan (BPD and/or a small kidney) were noted in 125 patients (82.8%). BPD according to the Goldraich classification13,14 was identified in 115 patients (76.2%). Table 2 lists findings by patient. Abnormal findings were identified on DMSA scan in 145 renal units (70.4%). Grade 5 VUR had a higher
(3) (54) (20) (11 mos–7.6 yrs)
(9) (50) (19) (8 mos–7.6 yrs)
rate of DMSA abnormality than grade 4 VUR (74 of 89 cases or 83% vs 71 of 117 or 60.7%, p ⬍0.001). BPD was identified in 133 renal units (64.6%). BPD was noted in 69 of 89 patients (77.5%) with grade 5 VUR vs 64 of 117 (55%) with grade 4 VUR (p ⬍0.001). When combining groups 1 and 2, BPD was observed in the upper, mid and lower pole in 33%, 27% and 40% of cases, respectively. Table 3 lists findings by renal unit. Table 4 shows the BPD rate by different grades of the modified Goldraich classification13,14 and the rate of small kidneys with dysplasia and hypoplasia. The NPD incidence was 11.9% (18 of 151 boys) for a rate of 3.67 NPDs/100 patients per year. Median patient age at NPD was 2.2 years (range 10 months to 4.8 years) (fig. 2). Febrile UTI was documented in 13 patients (72.2%) before NPD formation. Eight of 52 group 1 patients (15%) and 10 of 99 in group 2 (10%) had NPDs (p ⫽ 0.4). NPDs developed in 8 of 19 patients (42%) with voiding dysfunction. The NPD incidence was significantly higher in these cases (OR 8.8, 95% CI 2.92–26.92, chi-square 18.8, 1 df, p ⬍0.001). After circumcision 4 of 76 children (5.2%) had NPDs while NPDs were noted in 14 of 137 (10.2%) who were not offered circumcision or before circumcision (p ⫽ 0.3). Only 1 of the 14 children who underwent circumTable 2. BPD and small kidney initial DMSA scan findings by patient presentation
Overall Renal abnormality Unilat/total abnormality Bilat/total abnormality BPD Unilat/BPD Bilat/BPD
No. Group 1/Total No. (%)
No. Group 2/Total No. (%)
No. Overall/Total No. (%)
52/151 (34) 43/52 (83) 33/43 (77) 10/43 (23) 41/52 (79) 32/41 (78) 9/41 (22)
99/151 (66) 82/99 (83) 65/82 (79) 17/82 (21) 74/99 (75) 59/74 (80) 15/74 (20)
151 (100) 125/151 (83) 98/125 (78) 27/125 (22) 115/151 (76) 91/115 (79) 24/115 (21)
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Table 3. Initial BPD and small kidney findings on initial DMSA scan by renal unit presentation
Renal abnormality (BPD ⫹/or small kidney): Grade 4 Grade 5 Chi-square p Value Overall BPD: Grade 4 Grade 5 Chi-square p Value
No. Group 1/Total No. (%)
No. Group 2/Total No. (%)
No. Overall/Total No. (%)
52/78 (66.7)
93/128 (72.6)
145/206 (70.4)
19/37 33/41 6.176 0.012 49/78 18/37 31/41 4.954 0.026
52/80 (65) 41/48 (85) 5.309 0.02 84/128 (65.6) 46/80 (58) 38/48 (79) 5.319 0.02
71/117 (61) 74/89 (83) 12.236 ⬍0.001 133/206 (64.6) 64/117 (55) 69/89 (78) 10.537 0.0012
(51) (81)
(63) (49) (76)
cision in the neonatal period had a NPD. Three patients in whom NPDs developed after circumcision also had underlying voiding dysfunction but no documented febrile UTI. NPD developed in 20 renal units (18 patients). Of 133 renal units with BPD 13 (9.8%) had a NPD while NPD developed in 7 of 73 previously normal renal units (9.6%) (p ⬎0.9). Intervention Efficacy for Preventing Breakthrough UTI The incidence of breakthrough UTIs was highest in patients maintained on antibiotics only (table 5). The incidence appeared to be lowest in children who underwent circumcision, although followups were dissimilar.
No. Kidneys/Total No. (%) Group 1
Group 2
Overall
49/78 (63) 3 13
84/128 (66) 23 14
133/206 (65) 26 27
Totals 2/4 2/5
16 3 5
(33)
37 2 5
(44)
53 5 10
(40)
Totals 3/4 3/5
8 8 7
(16)
7 20 12
(8)
15 28 19
(11)
Totals 4/4 4/5
15 4 6
(31)
32 1 7
(38)
47 5 13
(35)
8 (10) 59/128 (46.1) 50 (85) 9 (15) 34 25
18 89 77 12 49 40
(14) (43.2) (87) (13)
Totals Small (hypoplasia ⫹ dysplasia): BPD No BPD Grade 4 VUR Grade 5 VUR
10 (20) 30/78 (38.5) 27 (90) 3 (10) 15 15
Antireflux Surgery Group Surgical treatment for VUR was done in 28 patients, 26 were uncircumcised and 2 underwent surgery after circumcision. Bilateral ureteral reimplantation was done in 19 patients, unilateral reimplantation was done in 5, unilateral reimplantation with contralateral nephrectomy was done in 3 and nephrectomy was done in 1 for a refluxing, nonfunctioning kidney. Five patients (17.9%) had a febrile UTI postoperatively. Two patients had more than 2 febrile UTIs and in 1 end stage renal disease developed. Delayed excretion on postoperative diuretic renal scan was documented in 3 patients (10.7%) (table 6). Two patients (7%) with failure to empty the bladder were treated with clean intermittent catheterization.
DISCUSSION
Table 4. BPD Goldraich classification by renal unit presentation
BPD (Goldraich/VUR grade): 1/4 1/5
Figure 2. Age at new scar formation in boys with high grade VUR.
Our study population represents a highly select group of patients who were considered at high risk. Although prenatal ultrasound is a common practice in Australia, only a third of our patients were diagnosed after investigation for prenatal hydronephrosis. The incidence of renal abnormalities (83%) or BPD (76%) was significantly high compared to most published data.16 –19 This may be explained by the inclusion of only grades 4 and 5 VUR in male patients. Renal parenchymal damage can generally be classified as congenital or acquired with UTI a major risk factor for scar pathogenesis.20,21 Many reports acknowledge the relationship between VUR and congenital defects (hypoplasia and dysplasia) but the high incidence of renal defects is mainly attributable to febrile UTI.21 In our study the BPD rate in the prenatal group was not different from that in patients who presented after UTI. This suggests that the etiology of renal defects is more likely congenital than infectious and the big bang theory is wrong but even the group that performed that study agreed that it is wrong.22,23 Also, screening patients
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Table 5. Breakthrough febrile UTIs by treatment group Antibiotics Only No. pts/No. UTI (%) Median followup (range) OR (95% CI) Chi-square p Value
137/62 (45.2) 38 Mos (10 mos–11 yrs)
with prenatal hydronephrosis by voiding cystourethrogram to identify those with VUR does not seem to prevent renal injury. The same renal injury rate is seen when waiting until the first UTI develops in these boys and then diagnosing VUR. Few studies address the incidence of new DMSA defects in infants with high grade VUR.19,24,25 Overall 18 patients (11.9%, 20 renal units or 9.7%) showed NPD. In 13 patients (72%) febrile UTI preceded defect formation, while 5 had normal urine cultures during followup. Our data suggest another major factor in NPD formation and renal function deterioration. Voiding dysfunction was an important risk factor for NPD in males with high grade VUR. NPD developed in 8 of 19 patients (44%) in this subgroup, significantly more than in the nonvoiding dysfunction group (10 of 132 or 7.6%). Four patients in the subgroup had no documented febrile UTI during followup. This raises the possibility of scarring due to high pressure sterile reflux, similar to that in patients with neurogenic bladder. BPD presence or absence on initial DMSA scan was not related to the risk of NPD. In fact, it was almost identical in the 2 groups, which challenges the concept that abnormal kidneys are at a higher risk for NPD. In the literature there is overwhelming evidence questioning the effectiveness of CAP for preventing febrile UTI.5 In our study CAP failed to prevent a large number of breakthrough UTIs. On the other hand, circumcision seemed to decrease the UTI risk in this group, although separating the effect of circumcision from the effect of prophylactic antibiotics and increasing age made analysis difficult. That is, most UTIs developed in the first year of life and in group 2 circumcision was done in older children. Patients were then older when they were followed and less likely to have a further UTI based on age.
After Circumcision 74/5 (6.7) 30 Mos (9 mos–5 yrs) 0.995 (0.03–0.24) 32.14, 1 df ⬍0.001
After Antireflux Surgery 28/5 (17.8) 15 Mos (8–29) 0.26 (0.09–0.72) 6.145, 1 df ⬍0.001
When deciding on treatment, the risks and harm of treatment must be balanced against the benefits. Circumcision is a relatively simple, inexpensive therapy that seems to be effective for preventing UTI. In contrast, cystoscopy with Deflux® injection is quite expensive with a 51% to 63% high grade VUR resolution rate postoperatively26 and the evidence that this decreases UTI is no better than the evidence that circumcision decreases UTI. Prophylaxis is also considerably less expensive but it does not seem to prevent UTI in many patients. Surgical correction for VUR with open ureteral reimplantation is the most expensive treatment but also the most effective treatment for resolving VUR. Unfortunately the complication rate of open reimplantation is relatively high in this patient group, approaching 10%. The reason for this is not clear8,9 but may be related to preexisting or subsequent abnormal bladder function. The international VUR study showed that obstruction after surgery tends to lead to renal scarring on IVP.2 Thus, this group is at high risk for renal scarring.
CONCLUSIONS Renal parenchymal damage was common in this patient cohort at 76%. The rate of DMSA defects was independent of presentation mode. The new renal defect formation rate was 11.9%. The presence or absence of renal defects on initial DMSA scan had no impact on the development of new defects during followup. Breakthrough febrile UTIs and voiding dysfunction were the main risk factors associated with new scars. Circumcision significantly decreased the incidence of breakthrough UTI and was associated with a lower rate of observed new defects.
Table 6. Patients with bilateral reimplantation and delayed excretion postoperatively
Age at surgery (mos) Complication side Intervention Outcome Voiding dysfunction
Pt 1
Pt 2
Pt 3
24 Rt Neg Whitaker test, noncompliant on clean intermittent catheterization, vesicostomy Stable Yes
22 Lt Clean intermittent catheterization
48 Bilat Unknown secondary ureteropelvic junction, infrequent voiding Improved at 1 yr No
Renal failure Yes
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coureteral reflux after reimplantation. J Urol 1987; 138: 1205. 9. Upadhayay J, Shekarriz B and Fleming P: Ureteral reimplantation in infancy: evaluation of long-term voiding function. J Urol 1999; 162: 1209. 10. Jodal U, Koskimies O, Hanson E et al: Infection pattern in children with vesicoureteral reflux randomly allocated to operation or long-term antibacterial prophylaxis. The International Reflux Study in Children. J Urol 1992; 148: 1650. 11. Risdon R: The small scarred kidney in childhood. Pediatr Nephrol 1993; 7: 361. 12. Report of the International Reflux Study Committee I: medical versus surgical treatment of primary vesicoureteral reflux—a prospective international reflux study in children. J Urol 1981; 125: 277. 13. Craig JC, Irwig L, Ford M et al: Reliability of DMSA for the diagnosis of renal parenchymal abnormality in children. Eur J Nucl Med 2000; 27: 1610. 14. Goldraich NP and Goldraich IH: Update on dimercaptosuccinic acid renal scanning in children with urinary tract infection. Pediatr Nephrol 1995; 9: 221. 15. Neveus T, von Gontard A, Hoebeke P et al: The standardization of terminology of lower urinary tract function in children and adolescents: report from the Standardisation Committee of the International Children’s Continence Society. J Urol 2006; 176: 314. 16. Hideo N, Hidehiro K, Ryuichiro K et al: Clinical characteristics of primary vesicoureteral reflux in infants: multicenter retrospective study in Japan. J Urol 2003; 169: 309.
17. Caione P, Ciofetta G, Morano S et al: Renal damage in vesico-ureteric reflux. BJU Int 2004; 93: 591. 18. Lama G, Russo M, De Rosa E et al: Primary vesicoureteric reflux and renal damage in first year of life. Pediatr Nephrol 2000; 15: 205. 19. Sjöström S, Jodal U, Sixt R et al: Longitudinal development of renal damage and renal function in infants with high grade vesicoureteral reflux. J Urol 2009; 181: 2277. 20. Goonasekera C and Dillon M: Hypertension in reflux nephropathy. BJU Int 1999; 83: 1. 21. Mohanan N, Colhoun E and Puri P: Renal parenchymal damage in intermediate and high grade infantile vesicoureteral reflux. J Urol 2008; 180: 1635. 22. Ransley PG: Vesicoureteric reflux: continuing surgical dilemma. Urology 1978; 12: 246. 23. Arnold AJ, Sunderland D, Rickwood AM et al: Bacterial factors in the formation of renal scars. An experimental study on the role of Escherichia coli P-fimbriation and hydrophobicity. Br J Urol 1993; 72: 549. 24. Chen J, Pugach J, West D et al: Infant vesicoureteral reflux: a comparison between patients presenting with a prenatal diagnosis and those presenting with a urinary tract infection. Urology 2003; 61: 442. 25. Ylinen E, Ala-Houhala M and Wikstrom S: Risk of renal scarring in vesicoureteral reflux detected either antenatally or during the neonatal period. Urology 2003; 61: 1238. 26. Elder JS, Diaz M, Caldamone AA et al: Endoscopic therapy for vesicoureteral reflux: a metaanalysis. I. Reflux resolution and urinary tract infection. J Urol 2006; 175: 716.
EDITORIAL COMMENT The paradigm for VUR treatment is changing. These authors indicate and substantiate that the most significant factors associated with new perfusion defects in boys with high grade VUR are the lack of breakthrough UTI, which directly correlates with circumcised status, and the presence or absence of voiding dysfunction. They question the effectiveness of antibiotic prophylaxis alone to prevent breakthrough UTI in boys with high grade VUR. Current antibiotic prophylaxis recommendations for VUR treatment in boys younger than 1 year is difficult to determine, given the lack of data on the prevention of acute pyelonephritis. Is the main problem with VUR the morbidity associated with an
increased risk of acute pyelonephritis or the potential acquisition of renal scarring, which in some cases has questionable significance? It may be simplistic to think that newborn circumcision and not antibiotics or surgical intervention may be the indicated treatment to prevent acute pyelonephritis and new perfusion defects in boys with high grade VUR. R. Guy Hudson Pediatric Urology Clinic Medical and Surgical Director Swedish Pediatric Specialty Care Seattle, Washington