- Email: [email protected]
Predicting Renal Outcomes in Children With Anterior Urethral Valves: A Systematic Review
Bladder
Predicting Renal Outcomes in Children With Anterior Urethral Valves: A Systematic Review Jonathan C. Routh,*,† Shawn M. McGee,*,‡ Richard A. Ashley, Yuri Reinberg and David R. Vandersteen§ From the Department of Urology, Mayo Medical School and Mayo Clinic, Rochester and Division of Urology, Children’s Hospital of Minnesota (YR, DRV), Minneapolis, Minnesota
Purpose: Prognostic information is limited on children with congenital anterior urethral valves or a diverticulum. We reviewed the literature and examined our clinical database to identify clinical features predicting a poor renal outcome, defined as azotemia, renal failure or death. Materials and Methods: We reviewed 97 English language studies of patients 18 years old or younger. Seven patients from our institutions were also included in analysis. After data abstraction we used multivariate models to define factors associated with outcomes of interest. Results: We identified 239 male patients with anterior urethral valves, of whom 139 had adequate data available for study inclusion. Of these patients 108 (78%) had normal renal function after treatment. On bivariate analysis vesicoureteral reflux (OR 22.4, p ⬍0.0001), pretreatment azotemia (OR 17.1, p ⬍0.0001), urinary tract infection (OR 3.3, p ⫽ 0.006), hydronephrosis (OR 10.0, p ⫽ 0.0004) and bladder trabeculation (OR 7.3, p ⫽ 0.01) were associated with renal failure or death while treatment method (p ⫽ 0.9), obstruction type (valve vs diverticulum, p ⫽ 0.4) and valve location (p ⫽ 0.6) were not. After adjusting for other factors only pretreatment azotemia (p ⫽ 0.0005) and vesicoureteral reflux (p ⫽ 0.01) remained associated with renal failure and/or death with a trend toward significance for urinary tract infection (p ⫽ 0.06). When all 3 factors were present, the odds of a poor renal outcome increased 25-fold (p ⫽ 0.005). Conclusions: Congenital anterior urethral obstruction in children has a generally good prognosis but may occasionally result in a poor renal outcome. The combination of pretreatment azotemia, vesicoureteral reflux and urinary tract infection is highly predictive of a poor renal outcome.
Abbreviations and Acronyms AUD ⫽ anterior urethral diverticulum AUV ⫽ anterior urethral valves UTI ⫽ urinary tract infection VUR ⫽ vesicoureteral reflux Study received institutional review board approval. Supported by Agency for Healthcare Research and Quality Grant T32-HS000063 (JCR). Supplementary material for this article can be obtained at http://www.pediatricsurgicalassociates. com/files/auv-appendix.pdf. * Equal study contribution. † Current address: Department of Urology, Children’s Hospital Boston, 300 Longwood Ave., HU-355, Boston, Massachusetts 02115. ‡ Current address: Adult and Pediatric Urology, 2351 Connecticut Ave. South, Suite 200, Sartell, Minnesota 56377. § Correspondence: Division of Urology, Children’s Hospitals of Minnesota, 2545 Chicago Ave. South, Suite 104, Minneapolis, Minnesota 55404 (telephone: 612-813-8000; FAX: 612-813-8005; e-mail: [email protected]).
Key Words: urethra, urinary tract infections, abnormalities, urethral obstruction, diverticulum CONGENITAL urethral obstruction may occur as a result of multiple etiologies, including urethral atresia, AUV, posterior urethral valves or urethral diverticulum. While renal outcomes secondary to posterior urethral valves are well described, there are sparse data on the prognosis and long-term renal function in children with the
less common entities AUV and/or AUD.1 This appears to be primarily due to the rarity of these disorders, as evidenced by the fact that few reports include more than a handful of patients with AUV or AUD. Previous reports of AUV and AUD varied in the assessment of anterior urethral obstruction with some inves-
0022-5347/10/1844-1615/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 184, 1615-1619, October 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.03.119
AND
RESEARCH, INC
www.jurology.com
1615
1616
PREDICTING RENAL OUTCOMES IN CHILDREN WITH ANTERIOR URETHRAL VALVES
tigators grouping the 2 entities together and others differentiating between them.2–5 Despite these differences it is well recognized that AUV and AUD can occur along the entire length of the anterior urethra, each may be associated with VUR, UTI, bladder trabeculation or hydroureteronephrosis, each may be treated with various techniques, including endoscopic valve ablation or urinary diversion, and in rare cases each may progress to renal failure.6 –11 However, the relative impact and importance of these factors to predict the renal outcome are unclear. Firlit et al previously reported a classification system based on proximal anatomical changes associated with AUV, which has also been applied to AUD.3 This system has been successfully used to classify anterior urethral obstruction cases but to our knowledge has not been evaluated in regard to its prognostic significance for renal function or overall outcome. To better describe outcomes in patients with these rare entities we systematically reviewed the cumulative urological literature on AUV and AUD. We analyzed these pooled data to determine whether the prognosis in a child could be predicted based on clinical presentation, treatment modality or anatomical classification.
PATIENTS AND METHODS Search Strategy We searched MEDLINE® and EMBASE® for English language studies published before December 2008 using certain exploded search terms, including anterior urethral valve, anterior urethral valves, anterior urethral diverticulum and anterior urethral diverticula. We also combined search results for the exploded terms anterior and urethra with the results of a second search using the terms valve or diverticulum. Reference lists of included studies were then hand searched to identify any missed studies. We particularly attempted to identify references published before 1966, which were not listed electronically.
Data Abstraction We defined study inclusion criteria as males younger than 18 years with congenital anterior urethral obstruction due to AUV or AUD. Patients without adequate renal outcome data or whose data were aggregated such that extracting individual, patient level data was impossible were included in the qualitative review but excluded from the quantitative review. All identified abstracts were reviewed to determine whether the study met inclusion criteria. For questionable studies we attempted to err on the side of inclusiveness. The full text of articles that reasonably appeared to meet selection criteria was then reviewed and, when they fully met inclusion criteria, the study data were abstracted. Abstracted data included the author description of obstruction type, presenting symptoms, the presence of proximal urethral dilatation, bladder trabeculation, hydronephrosis, VUR or UTI at diagnosis, renal function at
diagnosis, diagnosis method, valve site, treatment method and complications, persistent symptoms or urethral dilatation at last followup, renal function at last followup and whether definitive treatment was delayed, eg due to an initially missed diagnosis. The Firlit classification was also abstracted for patients with adequate clinical detail available (see Appendix).3 In addition to the patient cohort identified by our literature review, we also abstracted data on 7 patients seen at our institutions. For quantitative purposes these patients were treated as an individual study cohort. Institutional review board approval was obtained before data abstraction and analysis. The primary outcome of interest was patient renal function or death at followup. Thus, we defined the composite variable, poor renal outcome, as chronic renal insufficiency/azotemia, chronic renal failure, end stage renal disease or death. All reported deaths were assumed to be secondary to urethral obstruction unless otherwise specified in the published report. When data were missing, individuals were excluded only from analyses requiring that particular datum.
Statistical Methods We performed bivariate tests of association between predictor variables and the combined outcome variable of renal failure or death using the Fisher exact test, Cochran-Armitage trend or Wilcoxon rank sum test depending on data characteristics as well as by bivariate logistic regression models. We chose a priori to include covariates at p ⱕ0.2 on bivariate analysis in our multivariate models. As noted, the primary outcome variable was our composite renal outcome, defined as chronic renal insufficiency/ azotemia, chronic renal failure, end stage renal disease or death. Meta-regression was done using a series of nested logistic regression models. The final model was selected using model log-likelihood tests to determine the best predictive fit for the data set. The predictive ability of this final model was then compared to that of the Firlit anatomical classification.3 Model diagnostics revealed no significant violations of regression assumptions. All statistical analysis was done using SAS®, version 9.2. All tests were 2-sided with p ⬍0.05 considered significant.
RESULTS Systematic Review After screening the titles and/or abstracts of an initial 855 reports we reviewed the full text of 163 studies (see figure). Of these studies 97 with a total of 232 male children were included in our qualitative systematic review. Also, 7 previously unreported patients with AUV and/or AUD were included from our institutions for a total of 239 children identified by the systematic review. However, only 139 patients had adequate patient level data available and, thus, were eligible for inclusion in the quantitative review of renal outcomes.
PREDICTING RENAL OUTCOMES IN CHILDREN WITH ANTERIOR URETHRAL VALVES
1617
patient followup was 2.6 ⫾ 2.7 years (range 1 week to 14 years), including 2.5 ⫾ 21 vs 3.4 ⫾ 3.6 years in those with normal renal function vs renal insufficiency or failure, or death (Wilcoxon rank sum test p ⫽ 0.3). Of the patients 71 (51%) initially presented before age 1 year. The obstructing urethral lesion was most commonly reported as AUD (66%) and most commonly located in the bulbar (36%) or penile (35%) urethra. The most common presenting symptoms were penile swelling in 15% of cases, decreased urinary force of stream in 15% and post-void dribbling in 14%.
Systematic review
Patient Demographics Table 1 lists patient clinical data. Mean ⫾ SD age at diagnosis was 3.6 ⫾ 4.7 years (range 0 to 18), including 3.9 ⫾ 4.7 vs 2.7 ⫾ 4.7 years in those with normal renal function vs renal insufficiency or failure, or death (Wilcoxon rank sum test p ⫽ 0.15). Mean Table 1. Preoperative clinical features in all reported patients
Diagnosis: AUV AUD UTI at presentation: Present Absent Bladder trabeculation: Present Absent Any grade VUR: Present Absent Initial azotemia: Present Absent Initial hydronephrosis: Present Absent Initial urethral dilatation: Mild Moderate Severe Valve site: Bulbar Penoscrotal Penile Delayed diagnosis: Yes No
No. Normal Renal Function (%)
No. Renal Insufficiency, Failure or Death (%)
29 (34) 54 (64)
6 (26) 17 (74)
33 (33) 67 (67)
18 (62) 11 (38)
41 (58) 30 (42)
20 (91) 2 (9)
28 (33) 57 (67)
22 (92) 2 (8)
20 (20) 82 (80)
25 (81) 6 (19)
43 (43) 56 (57)
23 (88) 3 (12)
p Value (Fisher’s exact test) 0.6
0.009
0.004
⬍0.0001
Renal Outcomes Of the 139 children with adequate renal outcome data available 108 (78%) recovered normal renal function after treatment. Of the 31 children (22%) who did not return to normal renal function 17 (12%) had stable azotemia, 5 (4%) progressed to end stage renal disease requiring dialysis or transplantation and 9 (6%) died. Reporting investigators attributed death to urinary obstruction in all patients. Overall there was a trend toward improved renal outcomes with time based on the year of study publication. Before 1960, 7 of 15 patients (88%) progressed to renal failure or death while after 1960 only 24 of 124 (24%) progressed (p for trend ⫽ 0.02). However, after 1960 this trend appeared to stabilize with no further improvements in reports from 1960 to the current era (p for trend ⫽ 0.9). Renal Outcome Predictors On initial bivariate analysis the combined outcome of renal failure or death was associated with VUR (OR 22.4, p ⬍0.0001), pretreatment azotemia (OR 17.1, p ⬍0.0001), UTI (OR 3.3, p ⫽ 0.006), hydronephrosis (OR 10.0, p ⫽ 0.0004) and bladder trabeculation (OR 7.3, p ⫽ 0.01, table 2). Initial treatment method (p ⫽ 0.9), obstruction type (valve vs diverticulum, p ⫽ 0.4) and valve site (p ⫽ 0.6) were not. After adjusting for other factors only pretreatment azotemia (p ⫽ 0.0005) and VUR (p ⫽ 0.01)
⬍0.0001 ⬍0.0001
Table 2. Multivariate analysis predicting renal failure or death in patients with AUV or diverticulum
0.2 18 (23) 42 (54) 18 (23)
5 (28) 6 (33) 7 (39)
36 (41) 25 (27) 29 (32)
7 (26) 8 (30) 12 (44)
9 (9) 91 (91)
4 (15) 22 (85)
0.5
0.5
Any grade VUR Initial azotemia UTI Initial hydronephrosis Bladder trabeculation Age Urethral dilatation
Unadjusted OR (95% CI)
p Value
22.4 (4.9–102.0) 17.1 (6.2–47.2) 3.3 (1.4–7.8) 10.0 (2.8–35.4)
⬍0.0001 ⬍0.0001 0.006 0.0004
7.3 (1.6–33.7)
0.01
5.7 (0.3–117.4)
0.9 0.7
0.2 0.3
— —
(0.8–1.1) (0.2–2.7)
Adjusted OR (95% CI)* 8.8 12.4 3.2 1.9
(1.7–45.7) (3.0–51.3) (0.9–11.3) (0.2–18.8)
p Value 0.01 0.0005 0.06 0.6 0.3 — —
* Likelihood of renal failure or death after correcting for VUR and initial azotemia.
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PREDICTING RENAL OUTCOMES IN CHILDREN WITH ANTERIOR URETHRAL VALVES
remained associated with renal failure and/or death with a trend toward significance for UTI at presentation (p ⫽ 0.06, table 2). Despite the nonsignificance of UTI, including UTI as a covariate greatly improved the overall model fit and, thus, we retained it as a covariate. This model was highly predictive of renal failure or death (c ⫽ 0.91, 87% accuracy). The odds of a poor renal outcome increased more than 25-fold when all 3 factors were present. Comparison With Other Classification Systems The Firlit AUV classification3 was available in 111 patients, including types I to IV in 28, 37, 2 and 44, respectively. Poor renal outcomes developed more often in higher Firlit stage cases with progression to renal failure or death in 2 of 28 type I (7%), 3 of 37 type II (8%), 0 of 2 type III and 19 of 44 type IV cases (43%) (p ⬍0.0001 for trend). To predict the renal outcomes the Firlit anatomical classification with 61% accuracy (c ⫽ 0.76) was less predictive of renal failure or death than the clinical model using UTI, VUR and pretreatment renal status.
DISCUSSION Congenital anterior urethral obstruction due to AUV or AUD was initially described in 1906 by Watts.12 Multiple theories have been proposed as to the etiology of congenital AUV and/or AUD. Some groups have proposed that AUV is an incomplete form of urethral duplication or a result of intrauterine obstruction.13,14 Others think that they are the result of a ruptured cystic dilatation of Cowper’s duct or other periurethral gland.2,10 It is similarly unclear whether AUV and AUD are embryologically distinct entities that happen to commonly coexist or part of a continuum. Due to the rarity of these lesions and the lack of precision in describing them the exact etiology remains unclear and open to debate. Many reports show that the renal outcome of AUV and/or AUD is generally superior to that of other forms of infravesical obstruction, particularly compared to posterior urethral valves.1,3,10,15,16 Our analysis appears to support this belief. Of our patients with AUV or AUD 78% remained at or returned to normal renal functional status after treatment. An additional 12% of patients had stable renal function after treatment. These renal functional outcomes seem to be relatively unchanged with time with no significant change since 1960, as judged by study publication year. However, this trend may not be entirely accurate since many recent reports are case series including patients seen in the 1960s or earlier.10 Anterior urethral obstruction due to AUV or AUD is rare. This rarity has significantly restricted the
ability of previous investigators to determine the factors responsible for renal outcomes in these children. In circumstances such as these, systematic literature reviews may be useful.17 By combining the results of multiple case series we performed limited analysis to determine poor renal outcome predictors in cases of anterior urethral obstruction. The predictive ability of clinical parameters to predict renal outcomes was significant. Specifically combined azotemia, VUR and UTI at presentation highly predicted the post-therapy renal outcome. While UTI alone was not significantly predictive, the presence of VUR or preoperative azotemia doubled the odds of renal failure or death (OR 2.1) while all 3 increased those odds more than 25-fold (OR 27.5). This model was more predictive than the 1978 anatomical classification proposed by Firlit et al (see Appendix).3 Certain limitations inherent to systematic reviews should be considered when evaluating this study. As with any systematic review, our analysis was limited by the available data in included studies. The data that we abstracted were exclusively obtained from case reports and case series with a high degree of variability among studies in terms of the level of clinical detail reported in each. A basic principle of systematic reviews is that high quality results are only attainable by using high quality data. As such, if patients who were reported on and described with a high degree of clinical detail were systematically different from those not reported on or whose clinical details were less well described, it is likely that our results would be biased due to the selection of only well described children. Similarly only 139 of the 239 children (58%) whom we identified by our review had adequate patient level data, such that they could be included in the quantitative review. However, even in these children missing data were an issue. Particularly average followup was only 2.6 years and we did not have detailed renal function data on virtually all of our patients, including creatinine clearance. Instead we had to rely on investigator descriptions of normal or impaired renal function and their comments that patient deaths were ultimately attributable to urinary obstruction. Similarly we had virtually no data on long-term bladder function. This high attrition rate again raises the possibility of selection bias and may indicate that the generalizability of our findings is limited. In these circumstances individual patient level data are required to determine the prognostic value of clinical parameters. As such, we limited the generalizability of our findings to preserve accuracy. Although there are clearly limitations to this type of analysis, the rarity of conditions such as AUV or AUD limits the ability of groups at any single institution or even any group of institu-
PREDICTING RENAL OUTCOMES IN CHILDREN WITH ANTERIOR URETHRAL VALVES
tions to make statistically valid inferences as to the consequences and ramifications of this condition. A potential solution and an area of potentially fertile future research for these and other rare conditions would be to analyze large collective databases, eg the Agency for Healthcare Research and Quality Kids’ Inpatient Database, to validate or refute this prediction rule. Such an approach could also provide epidemiological insights into the incidence of AUV/ AUD.
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CONCLUSIONS Congenital anterior urethral obstruction in children has a generally good prognosis but may occasionally result in a poor renal outcome, such as renal insufficiency, renal failure or patient death. Our findings suggest that clinical data may predict the patient outcome more accurately than previously described anatomical classifications. Specifically the combination of pretreatment azotemia, VUR and UTI is highly predictive of a poor renal outcome.
APPENDIX Firlit AUV Classification3 Type
Urethral Involvement
Bladder Involvement
Upper Tract Involvement
I II III IV
Minimal proximal urethral distention Marked proximal urethral distention with well-defined urethral diverticulum Marked proximal urethral distention with urethral diverticulum Marked proximal urethral distention with urethral diverticulum
None None Mild bladder trabeculation Marked bladder trabeculation
None None Minimal ureteral ectasia, low grade VUR Marked hydroureteronephrosis, high grade VUR
REFERENCES 1. Casale AJ: Posterior urethral valves and other urethral anomalies. In: Campbell-Walsh Urology, 9th ed. Edited by AJ Wein, LR Kavoussi, AC Novick et al. Philadelphia: Saunders Elsevier 2007; vol 4, pp 3583–3603. 2. Williams D and Retik A: Congenital valves and diverticula of the anterior urethra. Br J Urol 1969; 41: 228. 3. Firlit R, Firlit C and King L: Obstructing anterior urethral valves in children. J Urol 1978; 119: 819. 4. Scherz H, Kaplan G and Packer M: Anterior urethral valves in the fossa navicularis in children. J Urol 1987; 138: 1211.
urethral valves in neonates and infants. J Urol 1987; 138: 107.
urethral valves: before and after endoscopic valve ablation. J Pediatr Urol 2007; 3: 295.
7. Cromie W, Cain M, Bellinger M et al: Urethral valve incision using a modified venous valvulotome. J Urol 1994; 151: 1053.
12. Watts SH: Urethral diverticula in the male with report of a case. Johns Hopkins Hospital Reports 1906; 13: 49.
8. Van Savage J, Khoury A, McLorie G et al: An algorithm for the management of anterior urethral valves. J Urol 1997; 158: 1030.
13. Texter J and Engel R: Anterior urethral valve as a cause for urinary obstruction: a case report. J Urol 1972; 107: 316.
9. Gupta D and Srinivas M: Congenital anterior urethral diverticulum in children. Pediatr Surg Int 2000; 16: 565.
5. Tank E: Anterior urethral valves resulting from congenital urethral diverticula. Urology 1987; 30: 467.
10. McLellan D, Gaston M, Diamond D et al: Anterior urethral valves and diverticula in children: a result of ruptured Cowper’s duct cyst? BJU Int 2004; 94: 375.
6. Rushton H, Parrott T, Woodward J et al: The role of vesicostomy in the management of anterior
11. Kajbafzadeh A, Payabvash S and Karimian G: Urodynamic changes in patients with anterior
14. Waterhouse K and Scordamaglia L: Anterior urethral valve: a rare cause of bilateral hydronephrosis. J Urol 1962; 87: 556. 15. Firlit C and King L: Anterior urethral valves in children. J Urol 1972; 108: 972. 16. Narasimhan K, Choudhary S and Kaur B: Anterior urethral valves. Indian Pediatr 2005; 42: 708. 17. Bergholz R and Wenke K: Polyorchidism: a metaanalysis. J Urol 2009; 182: 2422.
Predicting Renal Outcomes in Children With Anterior Urethral Valves: A Systematic Review Jonathan C. Routh,*,† Shawn M. McGee,*,‡ Richard A. Ashley, Yuri Reinberg and David R. Vandersteen§ From the Department of Urology, Mayo Medical School and Mayo Clinic, Rochester and Division of Urology, Children’s Hospital of Minnesota (YR, DRV), Minneapolis, Minnesota
Purpose: Prognostic information is limited on children with congenital anterior urethral valves or a diverticulum. We reviewed the literature and examined our clinical database to identify clinical features predicting a poor renal outcome, defined as azotemia, renal failure or death. Materials and Methods: We reviewed 97 English language studies of patients 18 years old or younger. Seven patients from our institutions were also included in analysis. After data abstraction we used multivariate models to define factors associated with outcomes of interest. Results: We identified 239 male patients with anterior urethral valves, of whom 139 had adequate data available for study inclusion. Of these patients 108 (78%) had normal renal function after treatment. On bivariate analysis vesicoureteral reflux (OR 22.4, p ⬍0.0001), pretreatment azotemia (OR 17.1, p ⬍0.0001), urinary tract infection (OR 3.3, p ⫽ 0.006), hydronephrosis (OR 10.0, p ⫽ 0.0004) and bladder trabeculation (OR 7.3, p ⫽ 0.01) were associated with renal failure or death while treatment method (p ⫽ 0.9), obstruction type (valve vs diverticulum, p ⫽ 0.4) and valve location (p ⫽ 0.6) were not. After adjusting for other factors only pretreatment azotemia (p ⫽ 0.0005) and vesicoureteral reflux (p ⫽ 0.01) remained associated with renal failure and/or death with a trend toward significance for urinary tract infection (p ⫽ 0.06). When all 3 factors were present, the odds of a poor renal outcome increased 25-fold (p ⫽ 0.005). Conclusions: Congenital anterior urethral obstruction in children has a generally good prognosis but may occasionally result in a poor renal outcome. The combination of pretreatment azotemia, vesicoureteral reflux and urinary tract infection is highly predictive of a poor renal outcome.
Abbreviations and Acronyms AUD ⫽ anterior urethral diverticulum AUV ⫽ anterior urethral valves UTI ⫽ urinary tract infection VUR ⫽ vesicoureteral reflux Study received institutional review board approval. Supported by Agency for Healthcare Research and Quality Grant T32-HS000063 (JCR). Supplementary material for this article can be obtained at http://www.pediatricsurgicalassociates. com/files/auv-appendix.pdf. * Equal study contribution. † Current address: Department of Urology, Children’s Hospital Boston, 300 Longwood Ave., HU-355, Boston, Massachusetts 02115. ‡ Current address: Adult and Pediatric Urology, 2351 Connecticut Ave. South, Suite 200, Sartell, Minnesota 56377. § Correspondence: Division of Urology, Children’s Hospitals of Minnesota, 2545 Chicago Ave. South, Suite 104, Minneapolis, Minnesota 55404 (telephone: 612-813-8000; FAX: 612-813-8005; e-mail: [email protected]).
Key Words: urethra, urinary tract infections, abnormalities, urethral obstruction, diverticulum CONGENITAL urethral obstruction may occur as a result of multiple etiologies, including urethral atresia, AUV, posterior urethral valves or urethral diverticulum. While renal outcomes secondary to posterior urethral valves are well described, there are sparse data on the prognosis and long-term renal function in children with the
less common entities AUV and/or AUD.1 This appears to be primarily due to the rarity of these disorders, as evidenced by the fact that few reports include more than a handful of patients with AUV or AUD. Previous reports of AUV and AUD varied in the assessment of anterior urethral obstruction with some inves-
0022-5347/10/1844-1615/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 184, 1615-1619, October 2010 Printed in U.S.A. DOI:10.1016/j.juro.2010.03.119
AND
RESEARCH, INC
www.jurology.com
1615
1616
PREDICTING RENAL OUTCOMES IN CHILDREN WITH ANTERIOR URETHRAL VALVES
tigators grouping the 2 entities together and others differentiating between them.2–5 Despite these differences it is well recognized that AUV and AUD can occur along the entire length of the anterior urethra, each may be associated with VUR, UTI, bladder trabeculation or hydroureteronephrosis, each may be treated with various techniques, including endoscopic valve ablation or urinary diversion, and in rare cases each may progress to renal failure.6 –11 However, the relative impact and importance of these factors to predict the renal outcome are unclear. Firlit et al previously reported a classification system based on proximal anatomical changes associated with AUV, which has also been applied to AUD.3 This system has been successfully used to classify anterior urethral obstruction cases but to our knowledge has not been evaluated in regard to its prognostic significance for renal function or overall outcome. To better describe outcomes in patients with these rare entities we systematically reviewed the cumulative urological literature on AUV and AUD. We analyzed these pooled data to determine whether the prognosis in a child could be predicted based on clinical presentation, treatment modality or anatomical classification.
PATIENTS AND METHODS Search Strategy We searched MEDLINE® and EMBASE® for English language studies published before December 2008 using certain exploded search terms, including anterior urethral valve, anterior urethral valves, anterior urethral diverticulum and anterior urethral diverticula. We also combined search results for the exploded terms anterior and urethra with the results of a second search using the terms valve or diverticulum. Reference lists of included studies were then hand searched to identify any missed studies. We particularly attempted to identify references published before 1966, which were not listed electronically.
Data Abstraction We defined study inclusion criteria as males younger than 18 years with congenital anterior urethral obstruction due to AUV or AUD. Patients without adequate renal outcome data or whose data were aggregated such that extracting individual, patient level data was impossible were included in the qualitative review but excluded from the quantitative review. All identified abstracts were reviewed to determine whether the study met inclusion criteria. For questionable studies we attempted to err on the side of inclusiveness. The full text of articles that reasonably appeared to meet selection criteria was then reviewed and, when they fully met inclusion criteria, the study data were abstracted. Abstracted data included the author description of obstruction type, presenting symptoms, the presence of proximal urethral dilatation, bladder trabeculation, hydronephrosis, VUR or UTI at diagnosis, renal function at
diagnosis, diagnosis method, valve site, treatment method and complications, persistent symptoms or urethral dilatation at last followup, renal function at last followup and whether definitive treatment was delayed, eg due to an initially missed diagnosis. The Firlit classification was also abstracted for patients with adequate clinical detail available (see Appendix).3 In addition to the patient cohort identified by our literature review, we also abstracted data on 7 patients seen at our institutions. For quantitative purposes these patients were treated as an individual study cohort. Institutional review board approval was obtained before data abstraction and analysis. The primary outcome of interest was patient renal function or death at followup. Thus, we defined the composite variable, poor renal outcome, as chronic renal insufficiency/azotemia, chronic renal failure, end stage renal disease or death. All reported deaths were assumed to be secondary to urethral obstruction unless otherwise specified in the published report. When data were missing, individuals were excluded only from analyses requiring that particular datum.
Statistical Methods We performed bivariate tests of association between predictor variables and the combined outcome variable of renal failure or death using the Fisher exact test, Cochran-Armitage trend or Wilcoxon rank sum test depending on data characteristics as well as by bivariate logistic regression models. We chose a priori to include covariates at p ⱕ0.2 on bivariate analysis in our multivariate models. As noted, the primary outcome variable was our composite renal outcome, defined as chronic renal insufficiency/ azotemia, chronic renal failure, end stage renal disease or death. Meta-regression was done using a series of nested logistic regression models. The final model was selected using model log-likelihood tests to determine the best predictive fit for the data set. The predictive ability of this final model was then compared to that of the Firlit anatomical classification.3 Model diagnostics revealed no significant violations of regression assumptions. All statistical analysis was done using SAS®, version 9.2. All tests were 2-sided with p ⬍0.05 considered significant.
RESULTS Systematic Review After screening the titles and/or abstracts of an initial 855 reports we reviewed the full text of 163 studies (see figure). Of these studies 97 with a total of 232 male children were included in our qualitative systematic review. Also, 7 previously unreported patients with AUV and/or AUD were included from our institutions for a total of 239 children identified by the systematic review. However, only 139 patients had adequate patient level data available and, thus, were eligible for inclusion in the quantitative review of renal outcomes.
PREDICTING RENAL OUTCOMES IN CHILDREN WITH ANTERIOR URETHRAL VALVES
1617
patient followup was 2.6 ⫾ 2.7 years (range 1 week to 14 years), including 2.5 ⫾ 21 vs 3.4 ⫾ 3.6 years in those with normal renal function vs renal insufficiency or failure, or death (Wilcoxon rank sum test p ⫽ 0.3). Of the patients 71 (51%) initially presented before age 1 year. The obstructing urethral lesion was most commonly reported as AUD (66%) and most commonly located in the bulbar (36%) or penile (35%) urethra. The most common presenting symptoms were penile swelling in 15% of cases, decreased urinary force of stream in 15% and post-void dribbling in 14%.
Systematic review
Patient Demographics Table 1 lists patient clinical data. Mean ⫾ SD age at diagnosis was 3.6 ⫾ 4.7 years (range 0 to 18), including 3.9 ⫾ 4.7 vs 2.7 ⫾ 4.7 years in those with normal renal function vs renal insufficiency or failure, or death (Wilcoxon rank sum test p ⫽ 0.15). Mean Table 1. Preoperative clinical features in all reported patients
Diagnosis: AUV AUD UTI at presentation: Present Absent Bladder trabeculation: Present Absent Any grade VUR: Present Absent Initial azotemia: Present Absent Initial hydronephrosis: Present Absent Initial urethral dilatation: Mild Moderate Severe Valve site: Bulbar Penoscrotal Penile Delayed diagnosis: Yes No
No. Normal Renal Function (%)
No. Renal Insufficiency, Failure or Death (%)
29 (34) 54 (64)
6 (26) 17 (74)
33 (33) 67 (67)
18 (62) 11 (38)
41 (58) 30 (42)
20 (91) 2 (9)
28 (33) 57 (67)
22 (92) 2 (8)
20 (20) 82 (80)
25 (81) 6 (19)
43 (43) 56 (57)
23 (88) 3 (12)
p Value (Fisher’s exact test) 0.6
0.009
0.004
⬍0.0001
Renal Outcomes Of the 139 children with adequate renal outcome data available 108 (78%) recovered normal renal function after treatment. Of the 31 children (22%) who did not return to normal renal function 17 (12%) had stable azotemia, 5 (4%) progressed to end stage renal disease requiring dialysis or transplantation and 9 (6%) died. Reporting investigators attributed death to urinary obstruction in all patients. Overall there was a trend toward improved renal outcomes with time based on the year of study publication. Before 1960, 7 of 15 patients (88%) progressed to renal failure or death while after 1960 only 24 of 124 (24%) progressed (p for trend ⫽ 0.02). However, after 1960 this trend appeared to stabilize with no further improvements in reports from 1960 to the current era (p for trend ⫽ 0.9). Renal Outcome Predictors On initial bivariate analysis the combined outcome of renal failure or death was associated with VUR (OR 22.4, p ⬍0.0001), pretreatment azotemia (OR 17.1, p ⬍0.0001), UTI (OR 3.3, p ⫽ 0.006), hydronephrosis (OR 10.0, p ⫽ 0.0004) and bladder trabeculation (OR 7.3, p ⫽ 0.01, table 2). Initial treatment method (p ⫽ 0.9), obstruction type (valve vs diverticulum, p ⫽ 0.4) and valve site (p ⫽ 0.6) were not. After adjusting for other factors only pretreatment azotemia (p ⫽ 0.0005) and VUR (p ⫽ 0.01)
⬍0.0001 ⬍0.0001
Table 2. Multivariate analysis predicting renal failure or death in patients with AUV or diverticulum
0.2 18 (23) 42 (54) 18 (23)
5 (28) 6 (33) 7 (39)
36 (41) 25 (27) 29 (32)
7 (26) 8 (30) 12 (44)
9 (9) 91 (91)
4 (15) 22 (85)
0.5
0.5
Any grade VUR Initial azotemia UTI Initial hydronephrosis Bladder trabeculation Age Urethral dilatation
Unadjusted OR (95% CI)
p Value
22.4 (4.9–102.0) 17.1 (6.2–47.2) 3.3 (1.4–7.8) 10.0 (2.8–35.4)
⬍0.0001 ⬍0.0001 0.006 0.0004
7.3 (1.6–33.7)
0.01
5.7 (0.3–117.4)
0.9 0.7
0.2 0.3
— —
(0.8–1.1) (0.2–2.7)
Adjusted OR (95% CI)* 8.8 12.4 3.2 1.9
(1.7–45.7) (3.0–51.3) (0.9–11.3) (0.2–18.8)
p Value 0.01 0.0005 0.06 0.6 0.3 — —
* Likelihood of renal failure or death after correcting for VUR and initial azotemia.
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PREDICTING RENAL OUTCOMES IN CHILDREN WITH ANTERIOR URETHRAL VALVES
remained associated with renal failure and/or death with a trend toward significance for UTI at presentation (p ⫽ 0.06, table 2). Despite the nonsignificance of UTI, including UTI as a covariate greatly improved the overall model fit and, thus, we retained it as a covariate. This model was highly predictive of renal failure or death (c ⫽ 0.91, 87% accuracy). The odds of a poor renal outcome increased more than 25-fold when all 3 factors were present. Comparison With Other Classification Systems The Firlit AUV classification3 was available in 111 patients, including types I to IV in 28, 37, 2 and 44, respectively. Poor renal outcomes developed more often in higher Firlit stage cases with progression to renal failure or death in 2 of 28 type I (7%), 3 of 37 type II (8%), 0 of 2 type III and 19 of 44 type IV cases (43%) (p ⬍0.0001 for trend). To predict the renal outcomes the Firlit anatomical classification with 61% accuracy (c ⫽ 0.76) was less predictive of renal failure or death than the clinical model using UTI, VUR and pretreatment renal status.
DISCUSSION Congenital anterior urethral obstruction due to AUV or AUD was initially described in 1906 by Watts.12 Multiple theories have been proposed as to the etiology of congenital AUV and/or AUD. Some groups have proposed that AUV is an incomplete form of urethral duplication or a result of intrauterine obstruction.13,14 Others think that they are the result of a ruptured cystic dilatation of Cowper’s duct or other periurethral gland.2,10 It is similarly unclear whether AUV and AUD are embryologically distinct entities that happen to commonly coexist or part of a continuum. Due to the rarity of these lesions and the lack of precision in describing them the exact etiology remains unclear and open to debate. Many reports show that the renal outcome of AUV and/or AUD is generally superior to that of other forms of infravesical obstruction, particularly compared to posterior urethral valves.1,3,10,15,16 Our analysis appears to support this belief. Of our patients with AUV or AUD 78% remained at or returned to normal renal functional status after treatment. An additional 12% of patients had stable renal function after treatment. These renal functional outcomes seem to be relatively unchanged with time with no significant change since 1960, as judged by study publication year. However, this trend may not be entirely accurate since many recent reports are case series including patients seen in the 1960s or earlier.10 Anterior urethral obstruction due to AUV or AUD is rare. This rarity has significantly restricted the
ability of previous investigators to determine the factors responsible for renal outcomes in these children. In circumstances such as these, systematic literature reviews may be useful.17 By combining the results of multiple case series we performed limited analysis to determine poor renal outcome predictors in cases of anterior urethral obstruction. The predictive ability of clinical parameters to predict renal outcomes was significant. Specifically combined azotemia, VUR and UTI at presentation highly predicted the post-therapy renal outcome. While UTI alone was not significantly predictive, the presence of VUR or preoperative azotemia doubled the odds of renal failure or death (OR 2.1) while all 3 increased those odds more than 25-fold (OR 27.5). This model was more predictive than the 1978 anatomical classification proposed by Firlit et al (see Appendix).3 Certain limitations inherent to systematic reviews should be considered when evaluating this study. As with any systematic review, our analysis was limited by the available data in included studies. The data that we abstracted were exclusively obtained from case reports and case series with a high degree of variability among studies in terms of the level of clinical detail reported in each. A basic principle of systematic reviews is that high quality results are only attainable by using high quality data. As such, if patients who were reported on and described with a high degree of clinical detail were systematically different from those not reported on or whose clinical details were less well described, it is likely that our results would be biased due to the selection of only well described children. Similarly only 139 of the 239 children (58%) whom we identified by our review had adequate patient level data, such that they could be included in the quantitative review. However, even in these children missing data were an issue. Particularly average followup was only 2.6 years and we did not have detailed renal function data on virtually all of our patients, including creatinine clearance. Instead we had to rely on investigator descriptions of normal or impaired renal function and their comments that patient deaths were ultimately attributable to urinary obstruction. Similarly we had virtually no data on long-term bladder function. This high attrition rate again raises the possibility of selection bias and may indicate that the generalizability of our findings is limited. In these circumstances individual patient level data are required to determine the prognostic value of clinical parameters. As such, we limited the generalizability of our findings to preserve accuracy. Although there are clearly limitations to this type of analysis, the rarity of conditions such as AUV or AUD limits the ability of groups at any single institution or even any group of institu-
PREDICTING RENAL OUTCOMES IN CHILDREN WITH ANTERIOR URETHRAL VALVES
tions to make statistically valid inferences as to the consequences and ramifications of this condition. A potential solution and an area of potentially fertile future research for these and other rare conditions would be to analyze large collective databases, eg the Agency for Healthcare Research and Quality Kids’ Inpatient Database, to validate or refute this prediction rule. Such an approach could also provide epidemiological insights into the incidence of AUV/ AUD.
1619
CONCLUSIONS Congenital anterior urethral obstruction in children has a generally good prognosis but may occasionally result in a poor renal outcome, such as renal insufficiency, renal failure or patient death. Our findings suggest that clinical data may predict the patient outcome more accurately than previously described anatomical classifications. Specifically the combination of pretreatment azotemia, VUR and UTI is highly predictive of a poor renal outcome.
APPENDIX Firlit AUV Classification3 Type
Urethral Involvement
Bladder Involvement
Upper Tract Involvement
I II III IV
Minimal proximal urethral distention Marked proximal urethral distention with well-defined urethral diverticulum Marked proximal urethral distention with urethral diverticulum Marked proximal urethral distention with urethral diverticulum
None None Mild bladder trabeculation Marked bladder trabeculation
None None Minimal ureteral ectasia, low grade VUR Marked hydroureteronephrosis, high grade VUR
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