The Correlation between Serial Ultrasound and Diuretic Renography in Children with Severe Unilateral Hydronephrosis

Author's Accepted Manuscript The Correlation Between Serial Ultrasound and Diuretic Renography in Children with Severe Unilateral Hydronephrosis Deborah L. Jacobson , Carl C. Flink , Emilie K. Johnson , Max Maizels , Elizabeth B. Yerkes , Bruce W. Lindgren , Dennis B. Liu , Ilina Rosoklija , Earl Y. Cheng , Edward M. Gong PII: DOI: Reference:

S0022-5347(18)42901-1 10.1016/j.juro.2018.03.126 JURO 15534

To appear in: The Journal of Urology Accepted Date: 27 March 2018 Please cite this article as: Jacobson DL, Flink CC, Johnson EK, Maizels M, Yerkes EB, Lindgren BW, Liu DB, Rosoklija I, Cheng EY, Gong EM, The Correlation Between Serial Ultrasound and Diuretic Renography in Children with Severe Unilateral Hydronephrosis, The Journal of Urology® (2018), doi: 10.1016/j.juro.2018.03.126. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.

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ACCEPTED MANUSCRIPT The Correlation Between Serial Ultrasound and Diuretic Renography in Children with Severe Unilateral Hydronephrosis

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Authors: 1. Deborah L. Jacobson, Division of Pediatric Urology, Department of Urology, Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; [email protected] 2. Carl C. Flink, Department of Radiology, University of Cincinnati, Cincinnati, Ohio; [email protected] 3. Emilie K. Johnson, Division of Pediatric Urology, Department of Urology, Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; [email protected] 4. Max Maizels, Division of Pediatric Urology, Department of Urology, Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; [email protected] 5. Elizabeth B. Yerkes, Division of Pediatric Urology, Department of Urology, Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; [email protected] 6. Bruce W. Lindgren, Division of Pediatric Urology, Department of Urology, Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; [email protected] 7. Dennis B. Liu, Division of Pediatric Urology, Department of Urology, Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; [email protected] 8. Ilina Rosoklija, Division of Pediatric Urology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; [email protected] 9. Earl Y. Cheng, Division of Pediatric Urology, Department of Urology, Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; [email protected] 10. Edward M. Gong, Division of Pediatric Urology, Department of Urology, Northwestern University, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; [email protected]

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Runninghead: Serial DR and RUS in Severe Hydronephrosis Key Words: child, hydronephrosis, kidney, radioisotope renography, ultrasonography

Correspondence: Edward Gong, MD [email protected] Ann & Robert H. Lurie Children’s Hospital of Chicago 225 E Chicago Ave, Box 24 Chicago, IL 60611-2605 Fax: 312-227-9412 Phone: 312-227-6340

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PURPOSE: While serial renal ultrasound is often used as an alternative to functional renal imaging among children followed for hydronephrosis, it is unclear whether a lack of hydronephrosis progression safeguards against loss of renal function. We seek to better characterize the association between findings on serial renal ultrasound and diuretic renography among children with severe unilateral hydronephrosis. METHODS: We retrospectively reviewed imaging among children <18 years with a history of severe unilateral hydronephrosis, two renal ultrasounds, and two diuretic renograms. Each pair of renal ultrasounds was interpreted by an independent, blinded diagnostic radiologist and compared with a contemporaneous diuretic renogram. Change in hydronephrosis was considered both as 1) a change in hydronephrosis grade or 2) any change by radiologist interpretation); a ≥5% change in split differential function was considered significant. Chi-squared and Spearman’s correlation analyses were performed. RESULTS: In total, 85 children were evaluated. Increased hydronephrosis was noted in 11.8% of children by grade and 32.9% of children by radiologist interpretation. Split differential renal function worsened by ≥5% in 17.6% of children. Overall, 13.3% of children with stable or decreased hydronephrosis developed worsening split differential function at an average of 11.8 months. When renal ultrasound and diuretic renograms were directly compared, the Spearman’s correlation was poor (r=0.24, CI [0.03-0.43]). CONCLUSIONS: The overall correlation between imaging modalities was poor, and 13.3% of children with stable or decreased hydronephrosis developed worsening split differential renal function. These findings are important to consider when counseling non-operatively managed children followed without diuretic renography.

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INTRODUCTION Antenatally detected hydronephrosis is one of the most commonly diagnosed congenital anomalies, and is reported in approximately 1% of all pregnancies.1-3 The incidence has more than doubled over the past decade.4 Obstruction at the ureteropelvic junction or along the course of the ureter is a modifiable cause of unilateral hydronephrosis in children. Persistent renal obstruction may lead to progressive loss of renal function,5 potentially necessitating renal replacement therapy or transplant. Hydronephrosis is generally diagnosed by renal ultrasound and is often categorized by Society of Fetal Urology (SFU)6 renal ultrasound grading parameters. While mild hydronephrosis (SFU grade 1-2) is often transient and physiologic, severe hydronephrosis (SFU grade 3-4) may be consequent to renal obstruction in up to 60% of patients.7 Other potential etiologies include vesicoureteral reflux, posterior urethral valves, ureteral obstruction, Eagle-Barrett syndrome, neurogenic bladder, urolithiasis, fibroepithelial polyps, post-surgical changes, adhesions, and malignancy. Renal ultrasound is the preferred modality for the diagnosis and monitoring of pediatric hydronephrosis because it is accessible, inexpensive, non-invasive, and non-ionizing. Increasing hydronephrosis on serial ultrasonography is often considered a risk factor for loss of renal function while stable or decreasing hydronephrosis is often considered a proxy for stable renal function.8-10 In previous patient cohorts, longitudinal evaluation of children with severe hydronephrosis has demonstrated improvement or resolution in approximately 90% of children followed nonoperatively.11, 12 Accepted indications for intervention include increasing hydronephrosis on serial ultrasound imaging, renal function loss, or symptomatology such as failure to thrive, pain, hematuria, or recurrent pyelonephritis.9 Unfortunately, renal ultrasound imaging is influenced by hydration status, bladder pathologies, and operator skill.13 Additionally, the ideal imaging interval is unknown and inter-rater reliability of SFU grading on renal ultrasound varies.13, 14 Renal parenchymal echogenicity can also be used to predict relative renal function on diuretic renography, but increases in renal echogenicity are often late-stage changes associated with permanent renal damage.15 Diuretic renography is the standard recommended test for evaluating split differential renal function (sDRF) among children with hydronephrosis.16, 17 Use of this modality necessitates intravenous radiotracer administration and urethral catheter placement. Therefore, the desire for close patient monitoring must be balanced with the morbidity of ionizing radiation and catheterization. While diuretic renography is often used to corroborate progressive ultrasound findings prior to operative intervention, its role in sequential monitoring among children with stable hydronephrosis is unclear. Our group has previously demonstrated that infants with unilateral SFU grade 3 hydronephrosis had preserved renal function on initial diuretic renogram, but the children were studied at a mean age of 2.3 months and longitudinal follow-up was not available.18 However, it is unknown whether a lack of increasing hydronephrosis on serial renal ultrasound is indicative of stable renal function. This study was performed to better characterize the association between findings on serial renal ultrasound and diuretic renography among children with severe unilateral hydronephrosis. We hypothesized that children with stable to decreasing hydronephrosis on serial ultrasound would have stable to improved sDRF on serial diuretic renogram imaging. METHODS We completed a retrospective cohort study of children aged less than 18 years with a history of unilateral SFU grade 3-4 hydronephrosis. Children were identified by querying the hospital Electronic Medical Record for Current Procedural Terminology (CPT) code 76770 (renal ultrasound) and 78708 (diuretic renogram). All children who had undergone at least two renal 3

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ultrasounds and at least two diuretic renograms between January 1, 2003 and July 30, 2016 were included in the initial cohort. A manual chart review was completed. Children were sequentially excluded based on pre-determined exclusion criteria including: 1) age greater than 18 years at the time of initial diuretic renogram, 2) time greater than 120 days between initial diuretic renogram and a corresponding renal ultrasound (if the time between studies was short, then children were excluded if the time between ultrasound and renogram imaging was greater than 2/3 of the spread between the two renograms), 3) comorbidities associated with bladder-level dysfunction (neurogenic bladder, posterior urethral valves, EagleBarrett syndrome, bladder exstrophy, and cloacal exstrophy), 4) comorbidities associated with uninterpretable diuretic renograms (solitary kidney, renal failure, renal transplant, known obstructive urolithiasis, ipsilateral vesicoureteral reflux, or ipsilateral duplicated collecting system), 5) inconsistent diuretic usage (diuretic use prior to one ultrasound but not the other), or 6) surgical intervention prior to imaging studies. Demographic characteristics were recorded and included as potential confounders. Children for whom demographic variables were unknown and those who underwent operative interventions at other institutions were excluded. Children with a history of surgical intervention prior to study imaging were also excluded. All study imaging was performed prior to surgical intervention on a given renal unit. Genitourinary imaging studies were reviewed in all children meeting inclusion criteria. Renal ultrasounds were used to quantify the degree of hydronephrosis (by SFU grading parameters) and diuretic renograms were used to quantify sDRF in the affected kidney (0-50%). Each diuretic renogram was correlated with a contemporaneous renal ultrasound; the initial renal ultrasound and diuretic renogram were chosen as index studies. A diagnostic radiologist reviewed index renal ultrasound images to establish index SFU grade. Children with confirmed unilateral SFU grade 3-4 hydronephrosis were included. Presence of contralateral SFU grade 1-2 hydronephrosis was permitted. An independent diagnostic radiologist reviewed each diuretic renogram and corresponding renal ultrasound. The radiologist was able to view studies sequentially, but was blinded to the initial image interpretation. For each study the radiologist documented the SFU grade,6 severity of hydroureter (absent, mild, moderate, or severe), laterality of hydronephrosis, sDRF, and status of the contralateral kidney were documented. The radiologist also provided a qualitative interpretation, noting whether hydronephrosis was decreased, stable, or increased between imaging studies. For each child, changes in degree of hydronephrosis were determined by either 1) change in SFU grade or 2) any change noted by the radiologist. These were compared with changes in diuretic renal imaging, with a ≥5% change in sDRF (i.e. change from 50%:50% to 45%:55%) considered significant.19 The relationships between renal function and degree of hydronephrosis, degree of hydroureter, surgical intervention, renal size, and patient demographics were also evaluated. Pairwise comparisons for hydronephrosis progression and changes in renal function among children with SFU grade 3 versus SFU grade 4 were evaluated using chi-square tests. Spearman’s correlation coefficients were calculated to evaluate the correlation between changes in the degree of hydronephrosis, by SFU grade or by the radiologist’s qualitative interpretation, and changes in sDRF. Analysis of covariance (ANCOVA) was performed to regress percent function loss on outcomes and covariates individually. Model covariates were chosen based on an a priori determination of risk, and included: age at index study, sex, race/ethnicity, insurance status, laterality, and index SFU grade. Statistical analyses were performed using StataSE, version 14.2 (StataCorp LLC, College Station TX) and SAS, version 9.4 (SAS Institute, Cary NC). Unless otherwise specified, a significance threshold of <0.05 was used.

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RESULTS Medical records for 596 consecutive children were reviewed. Overall, 511 children were excluded: 159 for comorbidities leading to bladder-level dysfunction or uninterpretable diuretic renograms, 166 for inappropriately timed imaging, 163 for imaging findings other than unilateral SFU grade 3-4 hydronephrosis +/- contralateral SFU grade 1-2 hydronephrosis, and 23 for inconsistent diuretic use (Figure 1). A total of 85 children with a mean age of 11.8 months (range 0.5-163.2) were followed for a mean 19.7 months (range 1.0-112.4) and were included in the primary analysis. Children were predominantly Caucasian (41/85, 48.2%), male (62/85, 72.9%), and privately insured (54/85, 63.5%). Hydronephrosis was predominantly SFU grade 3 (72/85, 84.7%) and associated with the left kidney (58/85, 68.2%; Table 1). The mean interval between renal ultrasounds was 19.6 months [SD 2.3 months]. The mean interval between diuretic renograms was 19.7 months. When assessed by renal ultrasound, the degree of hydronephrosis was stable or decreased in 75/85 children (88.2%) and increased in 10/85 (11.8%) by SFU grading parameters (Table 2). When assessed by diuretic renogram, sDRF was stable or improved in 70/85 children (82.4%) and worsened in 15/85 (17.6%) with a mean 11.9% decrease in sDRF (range 5-38%) over a mean 6 months of follow-up (range 3.1-62.1, Figure 2) Among children with stable or decreased hydronephrosis (by SFU grade), 65/75 children (86.7%) had stable to improved sDRF while 10/75 children (13.3%) had worsened sDRF at a mean 11.8 months of follow-up (range 3.1-22.8). Of these, all 11 children with decreased hydronephrosis had stable to improved sDRF. Findings were similar when hydronephrosis was classified by radiologist interpretation: 8/57 children (14.0%) with stable or decreased hydronephrosis had worsened sDRF. Among children with increasing hydronephrosis by SFU grade, 5/10 children (50.0%) had worsened sDRF; when radiologist interpretation was considered, 7/28 (25.0%) had worsened sDRF (Table 3). When increased hydronephrosis was defined as a change in the SFU grade on ANCOVA analysis, the overall Spearman’s correlation was poor (r=0.2, CI [0.03-0.43]). When increased hydronephrosis was defined by the radiologist’s interpretation (e.g. “increased hydronephrosis” without a change in SFU grade) on ANCOVA analysis, the overall correlation was poor (r=0.04, CI [0.18-0.25]). Model covariates including age at index study, sex, race/ethnicity, insurance status, laterality, and index SFU grade did not appreciably improve Spearman’s correlations between the two imaging modalities (Table 4).

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DISCUSSION Traditionally, children with mild hydronephrosis have been monitored for progression whereas children with severe hydronephrosis have undergone early surgical reconstruction, leading to roughly 3,300 operative pyeloplasties annually in the United States.20 Though primary pyeloplasty has a greater than 94% chance of long-term success,21 there are risks associated with surgical intervention and anesthesia in young children.22 Therefore, non-operative management of asymptomatic children without evidence of diminished renal function has gained favor in recent years.23 It is unclear whether a period of observation prior to reconstruction leads to irreversible renal loss among children with upper urinary tract obstruction. Much of the literature informing the debate is based on small retrospective series with divergent outcomes. Among non-operatively managed children, 86-93% of children with severe hydronephrosis had non-progression in several large series,9-12 while 50-88% had loss of renal function in several others.5, 24 The lack of clear consensus among available studies underscores the need for further investigation. In the setting of increased hydronephrosis by SFU grade, 50.0% of children had worsened sDRF. In the setting of increased hydronephrosis by the radiologist’s qualitative interpretation, 5

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25.0% of children had worsened sDRF. Among children with stable or decreased SFU grade, 13.3% had worsened sDRF; 14.1% of children with stable or decreased hydronephrosis by qualitative interpretation had worsened sDRF. When decreased SFU grade of hydronephrosis was considered separately, no patient had worsened sDRF whereas when decreased hydronephrosis by qualitative interpretation was considered separately, 9.1% of children had worsened sDRF. Importantly, there was not a significant association between findings on concomitant renal ultrasound and diuretic renogram in children with severe hydronephrosis. Studies comparing non-operative management to surgical intervention among children with severe hydronephrosis offer similarly conflicting evidence, with renal function loss reported among children waiting as little as 1-2 months before reconstruction versus reconstruction within 30 days.25 In the present study, children with stable hydronephrosis (by SFU grade) developed worsening sDRF at a mean 11.8 months, with changes noted in as few as 3.1 months. However, only two sets of images were evaluated for each child, and the timing between imaging studies was variable. When the interval between studies was short, the timing of any change in sDRF could be inferred. When the interval between studies was longer, it was unclear when in that period the change occurred. Management of children with severe unilateral hydronephrosis remains controversial, and our study is novel in its dual modality (renal ultrasound and diuretic renogram) longitudinal evaluation of radiographic outcomes. Chi and colleagues explored the use of renal ultrasound at the time of post-natal ultrasound among 97 children, and found that parenchymal echogenicity on renal ultrasound imaging parameters could be used to predict relative renal function on diuretic renography.15 Increases in renal echogenicity are evidence of later stage renal deterioration, however, and do not allow intervention prior to permanent renal damage with longitudinal followup. Ulman and colleagues prospectively studied non-operative management of 104 children with severe unilateral hydronephrosis and determined that non-operative management was appropriate in 78% of children.12 However, follow-up diuretic renograms were obtained on all patients and sDRF values were not reported. There are several important study limitations. First, this was a single-center retrospective cohort review. While chart review data is more granular than data extracted from national databases, our study population was limited to children seen at an urban, tertiary pediatric referral center in the Midwest. Diuretic renogram imaging obtained at an outside center and not available for review in our hospital system was not included in this analysis. Additionally, children of a certain race/ethnicity or payer mix may be over-represented in our sample. Second, our cohort was identified from a population of children undergoing diagnostic imaging tests in our hospital system. Our sample was, therefore, necessarily limited to children who had at least two diuretic renograms and two renal ultrasounds. Because diuretic renograms utilize ionizing radiation, they are utilized judiciously in a pediatric population and many potentially eligible children are not sent for repeat renogram imaging. Given these constraints, it is likely that our study is biased towards insured children and those monitored with diuretic renography due to heightened concern for progression based on factors not evaluated in our study. Third, despite controlling for patient age, comorbidities associated with bladder-level dysfunction, comorbidities associated with diuretic renogram interpretation, inconsistencies in study timing or diuretic administration, and history of surgical intervention, we do not have an entirely homogenous patient cohort. There is persistent heterogeneity in hydronephrosis grade, presence of ipsilateral hydroureter, and use of diuretics prior to ultrasound. Excluding children to control for these factors increase homogeneity at the expense of study power and generalizability. Finally, children were only followed to the time of their final diuretic renogram prior to surgical intervention (if any) at our institution. It is likely that children who were followed with serial imaging are less likely to experience renal deterioration than those who underwent early 6

ACCEPTED MANUSCRIPT surgical intervention. While we attempt to control for this bias by stratifying for index SFU grade, the relationship between hydronephrosis and sDRF outcomes is not precisely defined. Our study is generalizable to children with severe unilateral hydronephrosis undergoing non-operative management. Children with severe bilateral hydronephrosis or those with anomalies leading to bladder-level dysfunction represent a different population not considered in this analysis.

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CONCLUSIONS In this study, 13.3% of children with SFU grade 3-4 hydronephrosis developed worsened sDRF despite stable longitudinal renal ultrasound imaging. While substantial changes in renal ultrasound findings were generally associated with corollary changes on diuretic renogram, the overall correlation between imaging modalities was poor. These findings are important to consider when counseling parents regarding non-operative management of children with severe hydronephrosis who are followed without diuretic renography. Funding: None

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Conflict of Interest: None

Ethical Approval: Approved under the Ann & Robert H. Lurie Children’s Hospital of Chicago IRB

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Livera, L. N., Brookfield, D. S., Egginton, J. A. et al.: Antenatal ultrasonography to detect fetal renal abnormalities: a prospective screening programme. BMJ (Clinical research ed.), 298: 1421, 1989 Ek, S., Lidefeldt, K. J., Varricio, L.: Fetal hydronephrosis; prevalence, natural history and postnatal consequences in an unselected population. Acta Obstet Gynecol Scand, 86: 1463, 2007 Yang, H., Wang, Q., Luo, J. et al.: Ultrasound of urinary system and urinary screening in 14 256 asymptomatic children in China. Nephrology (Carlton), 15: 362, 2010 Mallik, M., Watson, A. R.: Antenatally detected urinary tract abnormalities: more detection but less action. Pediatr Nephrol, 23: 897, 2008 Ross, S. S., Kardos, S., Krill, A. et al.: Observation of infants with SFU grades 3-4 hydronephrosis: worsening drainage with serial diuresis renography indicates surgical intervention and helps prevent loss of renal function. J Pediatr Urol, 7: 266, 2011 Fernbach, S. K., Maizels, M., Conway, J. J.: Ultrasound grading of hydronephrosis: introduction to the system used by the Society for Fetal Urology. Pediatric Radiology, 23: 478, 1993 Lee, R. S., Cendron, M., Kinnamon, D. D. et al.: Antenatal hydronephrosis as a predictor of postnatal outcome: a meta-analysis. Pediatrics, 118: 586, 2006 De Grazia, E., Castagnetti, M., Cimador, M.: Surgical or conservative treatment of congenital hydronephrosis. Ten years' experience. Minerva Pediatr, 53: 275, 2001 7

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Correspondence: Deborah Jacobson, MD [email protected] Ann & Robert H. Lurie Children’s Hospital of Chicago 225 E Chicago Ave, Box 24 Chicago, IL 60611-2605 Fax: 312-227-9412 Phone: 615-495-2828

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Heinlen, J. E., Manatt, C. S., Bright, B. C. et al.: Operative versus nonoperative management of ureteropelvic junction obstruction in children. Urology, 73: 521, 2009 Karnak, I., Woo, L. L., Shah, S. N. et al.: Results of a practical protocol for management of prenatally detected hydronephrosis due to ureteropelvic junction obstruction. Pediatr Surg Int, 25: 61, 2009 Koff, S. A., Campbell, K. D.: The nonoperative management of unilateral neonatal hydronephrosis: natural history of poorly functioning kidneys. J Urol, 152: 593, 1994 Ulman, I., Jayanthi, V. R., Koff, S. A.: The long-term followup of newborns with severe unilateral hydronephrosis initially treated nonoperatively. J Urol, 164: 1101, 2000 Keays, M. A., Guerra, L. A., Mihill, J. et al.: Reliability assessment of Society for Fetal Urology ultrasound grading system for hydronephrosis. The Journal of Urology, 180: 1680, 2008 Kim, S. Y., Kim, M. J., Yoon, C. S. et al.: Comparison of the reliability of two hydronephrosis grading systems: the Society for Foetal Urology grading system vs. the Onen grading system. Clinical Radiology, 68: e484, 2013 Chi, T., Feldstein, V. A., Nguyen, H. T.: Increased echogenicity as a predictor of poor renal function in children with grade 3 to 4 hydronephrosis. J Urol, 175: 1898, 2006 Scharf, S. C., Blaufox, M. D.: Radionuclides in the evaluation of urinary obstruction. Semin Nucl Med, 12: 254, 1982 Shokeir, A. A.: The diagnosis of upper urinary tract obstruction. BJU Int, 83: 893, 1999 Erickson, B. A., Maizels, M., Shore, R. M. et al.: Newborn society of fetal urology grade 3 hydronephrosis is equivalent to preserved percentage differential function. J Pediatr Urol, 3: 382, 2007 Boubaker, A., Prior, J. O., Meuwly, J. Y. et al.: Radionuclide investigations of the urinary tract in the era of multimodality imaging. J Nucl Med, 47: 1819, 2006 Liu, D. B., Ellimoottil, C., Flum, A. S. et al.: Contemporary national comparison of open, laparoscopic, and robotic-assisted laparoscopic pediatric pyeloplasty. J Pediatr Urol, 10: 610, 2014 Silay, M. S., Spinoit, A. F., Undre, S. et al.: Global minimally invasive pyeloplasty study in children: Results from the Pediatric Urology Expert Group of the European Association of Urology Young Academic Urologists working party. J Pediatr Urol, 12: 229 e1, 2016 Sun, L. S., Li, G., Miller, T. L. et al.: Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA, 315: 2312, 2016 Chotipanich, C., Rubin, J., Lin, J. et al.: Clinical follow-up of children with low differential function on diuretic renogram. J Med Assoc Thai, 90: 754, 2007 Chertin, B., Pollack, A., Koulikov, D. et al.: Conservative treatment of ureteropelvic junction obstruction in children with antenatal diagnosis of hydronephrosis: lessons learned after 16 years of follow-up. European Urology, 49: 734, 2006 Jiang, D., Tang, B., Xu, M. et al.: Functional and Morphological Outcomes of Pyeloplasty at Different Ages in Prenatally Diagnosed Society of Fetal Urology Grades 3-4 Ureteropelvic Junction Obstruction: Is It Safe to Wait? Urology, 101: 45, 2017

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ACCEPTED MANUSCRIPT Table 1. Cohort Demographics SFU Grade 3 (N = 72)

Overall (N = 85)

8.6 3.7

[26.2] [0.5-67.5]

11.8 3.0

[17.9] [0.5-163.2]

21.8 [3.6-112.4]

11.4 12.7

[22.5] [1.0-60.8]

19.7 6.4

[15.8] [1.0-112.4]

(73.6%) (26.4%)

9 4

(69.2%) (30.8%)

62 23

(72.9%) (27.1%)

(48.6%)

6

(46.1%)

41

(48.2%)

(34.7%)

3

(23.1%)

28

(33.0%)

(8.3%) (7.0%)

1

(7.7%)

7

(8.2%)

(1.4%)

1 2

(7.7%) (15.4%)

6 3

(7.1%) (3.5%)

(63.9%) (33.3%) (2.8%)

9 4 0

(69.2%) (30.8%) (0.0%)

54 29 2

(63.5%) (34.1%) (2.4%)

(70.8%) (29.2%)

7 6

(53.8%) (46.2%)

58 27

(68.2%) (31.8%)

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25.1 [0.6-163.2]

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Age at Index Study (Months) Mean [SD] 12.4 Median [Range] 3.2 Duration of Follow-up (Months) Mean [SD] 21.1 Median [Range] 12.0 Sex Male 53 Female 19 Race/Ethnicity Caucasian, Non35 Hispanic/Latino Hispanic/Latino 25 Asian, NonHispanic/Latino 6 Black, NonHispanic/Latino 5 Other/Unknown 1 Insurance Private 46 Public 24 Other/Unknown 2 Hydronephrosis Laterality Left 51 Right 21

SFU Grade 4 (N = 13)

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Renal Ultrasound 1 Renal Ultrasound 2 Hydronephrosis Grade SFU Grade 0-2 7 (8.2%) SFU Grade 3 72 (84.7%) 59 (69.4%) SFU Grade 4 13 (15.3%) 19 (22.4%) Change in Hydronephrosis by SFU Grade Decreased/Stable 75 (88.2%) Increased 10 (11.8%) Qualitative Change in Hydronephrosis by Radiologist Interpretation Decreased/Stable 57 (67.1%) Increased 28 (32.9%) Degree of Ipsilateral Hydroureter Normal 62 (72.9%) 69 (81.2%) Mild Hydroureter 4 (4.7%) 4 (4.7%) Moderate Hydroureter 6 (7.1%) 3 (3.5%) Severe Hydroureter 13 (15.3%) 9 (10.6%)

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Stable/ Worsened Function Totals Significance Improved Function Change in Overall Hydronephrosis by SFU Grade Change Total 70 (82.4%) 15 (17.6%) 85 p = 0.004 Stable/Decreased 65 (86.7%) 10 (13.3%) 75 Increased 5 (50.0%) 5 (50.0%) 10 Qualitative Change in Overall Hydronephrosis by Radiologist Interpretation Total 70 (82.4%) 15 (17.6%) 85 p = 0.2 Stable/Decreased 49 (86.0%) 8 (14.0%) 57 Increased 21 (75.0%) 7 (25.0%) 28 Change in Index SFU Grade 3 Hydronephrosis by SFU Grade Change Total 59 (81.9%) 13 (18.1%) 72 p = 0.005 Stable/Decreased 54 (87.1%) 8 (12.9%) 62 Increased 5 (50.0%) 5 (50.0%) 10 Qualitative Change in Index SFU Grade 3 Hydronephrosis by Radiologist Interpretation Total 59 (89.1%) 13 (18.1%) 72 p = 0.1 Stable/Decreased 40 (87.0%) 6 (13.0%) 46 Increased 19 (73.1%) 7 (26.9%) 26 Change in Index SFU Grade 4 Hydronephrosis by SFU Grade Change Stable/Decreased 11 (84.6%) 2 (15.4%) 13 Qualitative Change in Index SFU Grade 4 Hydronephrosis by Radiologist Interpretation Stable/Decreased 9 (81.8%) 2 (18.2%) 11 Increased 2 (100.0%) 0 (0.0%) 2 Change in Ipsilateral Hydroureter Stable/Decreased 65 (82.3%) 14 (17.7%) 79 p = 1.0 Increased 5 (83.3%) 1 (16.7%) 6 Laterality Left 49 (84.5%) 9 (15.5%) 58 p = 0.5 Right 21 (77.8%) 6 (22.2%) 27

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ACCEPTED MANUSCRIPT Table 4. Multivariate Analysis

Range [ 0.03-0.43]

-0.03 0.12

[-0.30-0.25] [-0.23-0.45]

[ 0.03-0.47]

0.07 -0.20

[-0.17-0.29] [-0.68-0.39]

-0.03 0.45 -0.13

[-0.29-0.22] [-0.14-0.80] [-0.64-0.45]

[ 0.00-0.47]

0.06 -0.13

[-0.19-0.31] [-0.51-0.30]

[-0.29-0.33] [ 0.01-0.66] [-0.22-0.70]

-0.11 0.14 0.12

[-0.40-0.21] [-0.25-0.49] [-0.40-0.58]

M AN U

[-0.16-0.35] [ 0.14-0.88] [-0.12-0.81]

SC

[-0.03-0.49] [-0.11-0.54]

AC C

EP

TE D

Spearman’s Correlation All 0.24 Diuretic Use Prior to Ultrasound Lasix 0.25 No Lasix 0.24 SFU Grade Grade 3 0.26 Grade 4 Age < 6 months 0.10 6mo-1 year 0.64 >1 year 0.47 Sex Male 0.25 Female Race/Ethnicity White 0.02 Hispanic 0.38 Other 0.31

Qualitative Change in Hydronephrosis by Radiologist Interpretation Spearman’s Range Correlation 0.04 [-0.18-0.25]

RI PT

SFU Grade Change

1

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 1. Cohort Selection

1

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 2.

1

ACCEPTED MANUSCRIPT

KEY OF DEFINITIONS FOR ABBREVIATIONS

AC C

EP

TE D

M AN U

SC

RI PT

ANCOVA: analysis of covariance sDRF: Split differential renal function SFU: Society of Fetal Urology