VESICOURETERAL REFLUX AND COMPLETE URETERAL DUPLICATION. CONSERVATIVE OR SURGICAL MANAGEMENT?

0022-5347/05/1735-1725/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 173, 1725–1727, May 2005 Printed in U.S.A.

DOI: 10.1097/01.ju.0000154164.99648.ee

VESICOURETERAL REFLUX AND COMPLETE URETERAL DUPLICATION. CONSERVATIVE OR SURGICAL MANAGEMENT? KOUROSH AFSHAR, FRANK PAPANIKOLAOU, ROJA MALEK, DARIUS BAGLI, JAO L. PIPPI-SALLE AND ANTOINE KHOURY From the Division of Urology and Clinical Epidemiology, British Columbia’s Children’s Hospital (KA), Vancouver, British Columbia, and Division of Urology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

ABSTRACT

Purpose: The management of vesicoureteral reflux (VUR) in a duplicated collecting system (DS) is controversial. Available literature is sparse and it does not assess all co-factors. We compared the outcome of VUR in DS cases with VUR in single system (SS) cases, given similar clinical management in the 2 groups. Materials and Methods: A retrospective cohort study was done to compare the outcome of VUR in 35 children (44 units) with a DS and in 95 (150 units) with an SS. Patients with secondary reflux, incomplete duplication and ureterocele were excluded. Two groups were similar in terms of prognostic factors. Mean followup in the DS and SS groups was 43 and 48 months, respectively. Outcomes of interest were spontaneous resolution or uncomplicated persistence vs surgical correction. The same criteria were used to intervene surgically in the 2 groups. Results: In the DS group 24 of 35 patients (69%) underwent surgery compared with 25 of 95 (25%) in the SS group. Multivariate analysis showed an association between surgery due to complications and the presence of DS (p ⫽ 0.0001). Higher grade and female gender were independent predictors (p ⫽ 0.02 and 0.0007, respectively). The likelihood of undergoing surgery was the same for low grade VUR (I and II) in the DS and SS groups (p ⫽ 0.16). No resolution was seen in the duplex group with severe VUR at a mean followup of 42 months. Conclusions: Low grade VUR in DS cases has an outcome similar to that of VUR in SS cases. Females with moderate or high grade VUR and a DS should be treated differently because they present more often with complications. KEY WORDS: ureter, vesico-ureteral reflux, abnormalities, female, urinary tract infections

Vesicoureteral reflux (VUR) is one of the most common congenital abnormalities of the urinary tract with an estimated incidence of 10% in children.1 VUR, which is commonly identified in the course of investigating urinary tract infection (UTI) in children, increases the risk of pyelonephritis and may cause renal damage, hypertension and ultimately renal insufficiency. VUR may be associated with other congenital anomalies such as ureteral duplication, which occurs in 0.8% of the population.2 Therefore, the combination of VUR and duplication is frequently seen in pediatric urology practices. The natural course of VUR in a duplicated collecting system (DS) is not as well known as that of VUR in a single system (SS). This has resulted in a difference of opinion among urologists as how to treat this special group of patients. The literature is sparse and most studies lack a valid analysis of all prognostic factors. There has been a shift toward less aggressive management of primary VUR in SS cases in the last 2 decades. We have been managing VUR in DS cases similarly to that in SS cases in the last 10 years on the premise that duplication per se is not an indication for surgical intervention. To test this hypothesis we performed a retrospective cohort study to compare the outcome of VUR in DS and SS cases. The effects of covariables such as sex, age at diagnosis, grade and mode of presentation, were evaluated. MATERIALS AND METHODS

A total of 93 consecutive patients with reflux and ureteral duplication were identified from the database at the radiology department at our institution between 1995 and 2003. Patients with incomplete duplication, ureterocele, neurogenic bladder and outlet obstruction were excluded. A total of Submitted for publication August 11, 2004.

35 patients satisfied the inclusion criteria, including 13 males (37%) and 22 females (63%). Age at diagnosis was between 0 and 108 months (median 46). Four patients (11%) were diagnosed based on abnormal prenatal ultrasound and the remaining 89% presented with UTI. Followup was from 4 to 101 months (median 43). All except 1 patient had at least 2 voiding cystourethrograms and 1 ultrasound available. VUR was seen in 26 patients only in the lower pole moiety, in 6 in the ipsilateral upper and lower moieties, and in 3 in the lower moieties of bilateral duplex systems (total 44 refluxing units). Complete duplication was confirmed by cystoscopy in 6 patients with reflux to each pole. Of the patients 14 had reflux into the contralateral SS. VUR was low (I or II), intermediate (III) and high (IV or V) grade in 17 (39%), 15 (34%) and 12 units (27%), respectively. The SS cohort consisted of 95 randomly selected patients (150 units) using a random number table from the same period with primary VUR in an SS. Frequency matching was performed to enhance the comparability of baseline parameters between the 2 groups (see table). The outcomes of interest were spontaneous resolution of VUR, as shown on voiding cystourethrography, and surgical intervention. The indication for surgery was recorded. New renal scars, as shown by a new photopenic area on renal dimercapto-succinic acid scan, were recorded. Only febrile breakthrough UTI with a documented positive culture were included in this study. Kaplan-Meier and log rank analyses were performed to compare resolution and surgery rates. The Cox proportional hazard model was used for multivariate analysis of factors influencing the 2 outcomes using Statview software (SAS Institute, Cary, North Carolina). Proportions

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VESICOURETERAL REFLUX AND COMPLETE URETERAL DUPLICATION

Baseline parameters in duplex and single system groups No. sex (%): M F Median age at presentation (mos) % Presentation mode: Prenatal UTI Median followup (mos) % Grade: I–II III IV–V

Single

Duplex

p Value

39 (41) 56 (59) 24

13 (37) 22 (63) 10

0.8

15 85 42

11 88 46

51 31 18

39 34 27

0.9 0.9 0.3 0.3

were compared using the chi-square test with the Yates correction and ORs with the 95% CI were calculated. RESULTS

Figure 1 shows the overall outcome in the 2 groups. Of 35 patients 24 (69%, 28 of 44 units or 64%) with duplication and 24 of 95 (25%, 44 of 150 units or 29%) with a single system underwent surgery (fig. 1). This difference was statistically significant on univariate analysis (log rank p ⫽ 0021, fig. 2). Similar indications were used for surgical intervention in the 2 groups. The indication for surgery in duplex systems was febrile breakthrough UTI in 17 patients (71%), new renal scar formation in 3 (13%) and persistent VUR with parental preference in 4 (17%). Seven of the 17 patients with breakthrough UTI showed new scars on dimercapto-succinic acid scan done 6 months after infection. In the SS group VUR was corrected surgically because of breakthrough febrile UTI in 8 patients (32%), a new renal scar in 6 (24%), and persistent VUR with parental preference in 10 (44%). More patients underwent surgery due to breakthrough infection or new renal scars in the DS than in the SS group (OR 3.5, 95% CI 1.2 to 10.9, Yates corrected chi-square p ⬍0.0001). Multivariate analysis using the Cox model was performed to adjust for the effect of sex, grade, age at diagnosis and mode of presentation in the 2 groups. Duplex anatomy, female sex, high grade and younger age at diagnosis were independent factors for an increased chance of undergoing surgery (p ⫽ 0.007, 0.003, 0.008 and 0.004, respectively). The VUR resolution rate was significantly lower in the DS than in the SS group, as shown by Kaplan-Meier analysis (log rank p ⫽ 0.0014, fig. 3). At 5 years almost 50% of SS VUR had resolved compared with only 20% of DS VUR. When subset analysis was performed according to reflux grade, the proportion of units with spontaneous resolution was not significantly different for the low grade (Yates corrected chi-square p ⫽ 0.07, log rank p ⬎0.05). However, time to resolution was longer in the DS group. Half of the refluxing units resolved in 54 months in the SS group vs 84 months in the DS group. High grade reflux (III or greater) in the DS group showed a significantly lower

FIG. 1. Overall outcome of reflux in 2 groups

FIG. 2. Kaplan-Meier curve for surgery

FIG. 3. Kaplan-Meier curve for overall resolution

resolution rate (log rank corrected p ⫽ 0.02). In fact, only 7% of grade III and none of grades IV and V reflux resolved. Multivariate analysis using the Cox proportional hazard model was used to explore the effect of DS anatomy, grade, sex, age at diagnosis and mode of presentation. Duplex anatomy and high grade (III or greater) VUR significantly lowered the chance of resolution (p ⫽ 0.002 and 0.017, respectively). DISCUSSION

Our understanding of the natural history and pathophysiology of VUR has improved in the last 30 years. The impact of various factors on outcome has been recognized. For example, higher grade, older age at diagnosis, postnatal presentation and voiding dysfunction are associated with lower resolution rates.3–5 In addition, it is accepted that in the absence of infection primary VUR rarely, if ever, results in renal damage. This new clinical perspective of VUR has shifted management from a primarily surgical approach to more conservative medical treatment, that is antibiotic prophylaxis and voiding dysfunction treatment. There is general agreement among pediatric urologists that absolute indications for surgical correction are breakthrough febrile UTIs and new renal scars. Relative indications include noncompliance with or contraindication to medical treatment, persistent VUR with no improvement and parental preference. VUR grade and unilaterality vs bilaterality are also important factors in the decision making process.3 Traditionally patients with certain associated congenital anomalies have

VESICOURETERAL REFLUX AND COMPLETE URETERAL DUPLICATION

been subject to more aggressive treatment based on the assumption that their clinical outcome is poor. Ureteral duplication, which is the most common congenital anomaly associated with VUR, is a prime example. However, many groups have questioned the aggressive approach to these patients. Although there have been several studies in the past exploring the outcome of VUR in DS cases, most of them have shortcomings undermining their internal or external validity. Fehrenbaker et al reported a case series of 25 children in whom conservative management failed and surgical correction was done.6 The group concluded that all VUR in DS cases should be treated surgically. No definitions of conservative management or failure were provided and it is not clear why the patients underwent surgery. No control group was described. Lee et al reported a case series of 105 children with VUR in a DS.7 They excluded patients with severe VUR and renal damage, and followed only 38. They reported an 85% resolution and 10% complication rate in this group, and concluded that there was a similarity in outcome with that of VUR in SS cases. This study is not generalizable because it involved a select group of patients. There was no control group or statistical analysis to support the conclusion. Peppas et al described a retrospective cohort study in 56 children with VUR in a DS.8 They included all grades and compared the resolution rate to that of VUR in an SS. They concluded that, although patients with VUR in a DS are more likely to undergo surgery, it is not necessarily a surgical problem. They did not give any information other than grade about controls. It is not clear if cases and controls were comparable concerning any other variables, such as sex or age. They also acknowledged that the study was biased due to surgeon preference to operate for a DS. No statistical analysis was presented to compare the outcomes and support the conclusion. Husman and Allen reported a historical cohort study in 60 children with low grade VUR in a DS.9 A control group matched for age, sex, race and VUR grade was described for patients with VUR in an SS. The study only included low grade VUR. Median followup was only 2 years in the study group. They concluded that low grade VUR in a DS is less likely to resolve. This finding may be the result of short followup. Conversely in a similar matched study BenAmi et al concluded that the resolution rate is similar in low grade VUR in SS and DS cases.10 Patients with high grade VUR were excluded. Median followup is not mentioned. The current study confirms the common idea that low grade VUR in a DS has an outcome similar to that in an SS and it should be managed conservatively. The proportion of patients with grades I and II VUR with spontaneous resolution was not significantly different in the DS vs SS groups (Yates corrected chi-square p ⫽ 0.07). However, resolution occurred markedly later in the DS group, since there was a 30-month difference in the 2 groups for half of the units to stop refluxing. Our findings about high grade reflux are rather distinctive, in the sense that most previous studies excluded this group of patients. We noted that the resolution rate was significantly lower for high grade VUR in a DS (p ⫽ 0.02). Multivariate analysis using the Cox proportional hazard model identified duplex anatomy and grade as independent predictors of resolution. Only 7% of the units with grade III and none of those with grades IV or V VUR resolved at a median followup of 33 months. The development of new renal scars was not different in the 2 groups, that is 3 of 35 patients with a DS and 5 of 95 with an SS (OR 95% CI 0.48 to 9.25, Yates corrected p ⫽ 0.77). However, the likelihood of undergoing surgery in general, or due to the absolute indications of breakthrough infections or new renal scars was significantly higher for VUR in a DS (log rank p ⫽ 0.002). We assessed the impact of several prognostic factors on multivariate analysis and observed that, except for duplex anatomy, female sex, younger age at diagnosis and high grade reflux are risk factors for breakthrough UTI, new renal scars and undergoing surgery.

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A potential pitfall in the analysis our findings is the fact that more patients underwent surgery because of persistent VUR and parental preference in the SS group. The difference was not statistically significant (Yates corrected chi-square p ⫽ 0.11). This indication is obviously less objective and more open to physician interpretation. Bias may be introduced by operating in patients who may have had a chance of spontaneous resolution. The net effect is artificially to inflate the likelihood of surgery in an SS. Since our data showed a significant increase in the likelihood of surgery in a DS, one can conclude that, even if this assumption were correct, the magnitude was not large enough to change the results. In other words, adjusting the data for this factor would only confirm the current findings. To be more conservative we performed sensitivity analysis by decreasing the percent of patients who underwent surgery due to parental preference from 44% in the SS group to 22%. The log rank test still showed a significant difference between the 2 groups (p ⫽ 0.04). We acknowledge that our study has some limitations. The retrospective collection of data may have lowered its quality. We did not have enough data to assess the impact of voiding dysfunction. We do not expect that this was a source of systematic error because to our knowledge there is no evidence of an association between a DS and voiding dysfunction. However, random error is still possible. For example, if purely by chance more patients in the DS group had voiding dysfunction, at least part of our findings could be attributed to the uneven distribution of this factor in the 2 groups. This emphasizes the importance of prospective data collection. CONCLUSIONS

The management of VUR in a duplicated system should be based on multiple clinical factors, mainly the severity of VUR. Low grade VUR could be managed conservatively, much like VUR in SS cases, because there is substantial chance for resolution. Resolution will take longer to occur in DS cases. High grade reflux in patients with a DS, especially in young females, has a poor clinical outcome with lower resolution rates and a higher likelihood of infectious complications. Therefore, a more aggressive approach is warranted in this subset of patients. REFERENCES

1. Atala, A. and Keating, M. A.: Vesicoureteral reflux and megaureter. In: Campbell’s Urology, 8th ed. Edited by P. C. Walsh, A. B. Retik, E. D. Vaughan, Jr. and A. J. Wein. Philadelphia: W. B. Saunders Co., sect IX, vol. 3, chapt. 59, p. 2054, 2002 2. Schlussel, R. N. and Retik, A.: Ectopic ureter, ureterocele and other anomalies of the ureter. In: Campbell’s Urology, 8th ed. Edited by P. C. Walsh, A. B. Retik, E. D. Vaughan, Jr. and A. J. Wein. Philadelphia: W. B. Saunders Co,. sect. IX, vol. 3, chapt. 58, p. 2038, 2002 3. Elder, J. S., Peters, C. A., Arant, B. S., Jr., Ewalt, D. H., Hawtrey, C. E., Hurwitz, R. S. et al: Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol, 157: 1846, 1997 4. Koff, S. A., Wagner, T. T. and Jayanthi, V. R.: The relationship among dysfunctional elimination syndromes, primary vesicoureteral reflux and urinary tract infections in children. J Urol, 160: 1019, 1998 5. Farhat, W., McLorie, G., Geary, D., Capolicchio, G., Ba¨gli, D., Merguerian, P. et al: The natural history of neonatal vesicoureteral reflux associated with antenatal hydronephrosis. J Urol, 164: 1057, 2000 6. Fehrenbaker, L. G., Kelalis, P. P. and Strickler, G. B.: Vesicoureteral reflux and ureteral duplication in children. J Urol, 107: 862, 1972 7. Lee, P. H., Diamond, D. A., Duffy, P. G. and Ransley, P. G.: Duplex reflux: a study of 105 children. J Urol, 146: 657, 1991 8. Peppas, D. S., Skoog, S. J., Canning, D. A. and Belman, A. B.: Nonsurgical management of primary vesicoureteral reflux in complete ureteral duplication: is it justified? J Urol, 146: 1594, 1991 9. Husmann, D. A. and Allen, T. D.: Resolution of vesicoureteral reflux in completely duplicated systems: fact or fiction? J Urol, 145: 1022, 1991 10. Ben-Ami, T., Gayer, G., Hertz, M., Lotan, D. and Boichis, H.: The natural history of reflux in the lower pole of duplicated collecting systems: a controlled study. Pediatr Radiol, 19: 308, 1989