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Value of diagnosis imaging in the evaluation of the severity of histological lesions in duplex systems
Journal of Pediatric Urology (2014) 10, 361e367
Value of diagnosis imaging in the evaluation of the severity of histological lesions in duplex systems Alice Faure a,*, Thierry Merrot a, Quentin Sala b, Kathia Chaumoitre c, Jean-Michel Guys d, Brigitte Bourliere-Najean e, Julia Torrents f, Olivier Mundler b, Eric Lechevallier g, Pierre Alessandrini a a
Department of Pediatric Surgery, Hospital Nord, APHM, Aix-Marseille University, Chemin des Bourrely, Marseille 13015, France b Department of Nuclear Medicine, Hospital Timone, APHM, Aix-Marseille University, Marseille, France c Department of Medical Imaging, Hospital Nord, APHM, Aix-Marseille University, Marseille, France d Department of Pediatric Surgery, Hospital Timone, APHM, Aix-Marseille University, Marseille, France e Department of Pediatric Radiology, Hospital Timone, APHM, Aix-Marseille University, Marseille, France f Department of Pathology, Hospital Timone, APHM, Aix-Marseille University, Marseille, France g Department of Urology, Hospital Conception, APHM, Aix-Marseille University, Marseille, France Received 29 May 2013; accepted 5 October 2013 Available online 5 November 2013
KEYWORDS Pole nephrectomy; Duplex systems; Magnetic resonance urography; Ureterocele; Split renal function
Abstract Objective: In order to determine the effectiveness of imagery in the assessment of the severity of histological lesions in duplex systems in children we compared histology results from heminephrectomies with diagnosis imaging findings [renal ultrasound (US), scintigraphy, unenhanced and contrast-enhanced magnetic resonance imagery (MRI)]. Materials and methods: Between 2007 and 2013, 34 children with duplex system underwent surgery. The results from US (n Z 34), dimer captosuccinic acid scintigraphy (n Z 23) and MRI (n Z 16) were compared with histological data. Five histological lesions were found (chronic interstitial inflammation, interstitial fibrosis, tubular atrophy, glomerulosclerosis and dysplasia) and categorized as severe (>25%) or moderate (25%). Results: Severe histological lesions were found in 76.5% and moderate lesions in 23.5%. Radiological features were compared with histological results. In US, severe parenchymal thinning was associated with chronic interstitial inflammatory. The absence of parenchymal enhancement and/or severe cortical thinning in MR urography (MRU) was significantly
*Corresponding author. Tel.: þ33 4 91 96 86 36; fax: þ33 4 91 96 86 38. E-mail address: [email protected] (A. Faure). 1477-5131/$36 ª 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpurol.2013.10.009
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A. Faure et al. associated with interstitial fibrosis. All poorly functioning poles were associated with severe histological lesions (p Z 0.091), but not to a specific category of lesions. Conclusions: MRI sensibility was excellent (90%) in the diagnosis of poorly functioning pole. Severe thinning on US and minimal pole function on MRU can be used to predict the severity of histological lesions. ª 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Introduction Duplex systems are one of the most common anomalies of the upper urinary tract collecting system in children (0.5e1.25% on a series of autopsies) [1,2]. A vesicoureteral reflux (VUR) in the lower pole of a duplex system, or an obstruction of the upper urinary tract by a ureterocele or by an ectopic ureter can be responsible for loss of cortical function associated with significant parenchymal lesions. Current imagery techniques make it possible to characterize the duplex system and to help therapeutic decisions. A heminephrectomy is indicated for a poorly functioning pole associated with upper urinary tract infections or for incontinence due to ectopic ureter. Magnetic resonance urography (MRU) has been successfully used for the evaluation of pediatric urinary tract disease and is the most accurate test for the diagnosis of complications associated with duplex systems [3,4]. It is possible to study the anatomy and function of the affected renal parenchyma with MRU [5]. Unlike renal scintigraphy [dimer captosuccinic acid (DMSA) and mercaptoacetyltriglycine (MAG-3)], with MRU it is possible to identify an obstructive syndrome and/or an ectopic ureter including in renal units with poorly function without using ionizing radiation [6e8]. There are no studies in the literature that compare functional MRU results with histological lesions from pathologic poles in duplex systems. The objective of this study was to compare diagnosis imaging and the results with histological findings from heminephrectomy in order to determine the role of MRU in the evaluation of the severity of histological lesions in duplex systems.
Materials and methods Between 2007 and 2013, data were collected from three referral centers concerning 34 children who underwent heminephrectomies for a non-functioning pole among 160 duplex systems recorded in total. An analysis comparing unenhanced and contrast-enhanced magnetic resonance imagery (MRI) and histological findings was conducted using clinical data and the medical imagery. Two pediatric radiologists, unaware of the clinical history, surgical procedures and histological lesions reviewed preoperative imagery. The indications for surgery were a poorly functioning pole and urinary tract infections and/or incontinence in the case of extravesical ectopic ureter. All children aged between 0 and 18 years old who underwent a heminephrectomy were included. The exclusion criteria were incomplete medical files, bifid system, duplex
system that had been operated on but without heminephrectomy (ureteral reimplantation of both ureters, uretero-ureterostomy, pyeloplasty for ureteropelvic junction obstruction, nephrectomy) and duplex system that had been closely monitored. A renal ultrasound (US) was systematically performed for the preoperative evaluation and was sometimes associated with a voiding cystourethrography (VCUG) in order to search for VUR (grade IeV according to international recommendations) [9]. Parenchymal renal thinning was evaluated and categorized as moderate (cortical thickness > 1.5 mm) or severe (cortical thickness < 1.5 mm). The aspect and degree of hydronephrosis was also examined and evaluated according to the Society for Fetal Urology (SFU) grading system [10]. Static renal scintigraphy with 99 m technetium (Tc) DMSA was performed on 13 children (38%) with a dose of 1 MBq/kg. A local, or absence of, uptake was considered abnormal and indicated a restricted activity to the pole. A poorly functioning pole was arbitrarily defined as <5% of the global function. In three centers, 16 children (47%) underwent a MRI using a Tesla 1.5 MRI with sedation adapted to age in order to limit movement-related artifacts. Infants younger than 6 months were not sedateddadequate immobilization was obtained after feeding. Children younger than 5 years were placed in supine position on a plexiglas plate with restraining straps. Some examinations were performed with general anesthesia. The exploratory protocol included morphological T2weighted sequences in three planes in thin slices (4e5 mm thickness) then in thick-slice heavily T2-weighted sequences for anatomical display or fluid-filled structures. Functional examination was performed using contrastenhanced T1-weighted sequences. Gadolinium (0.1 ml/kg) was injected at the same time as furosemide (0.5 mg/kg, maximum 20 mg). The acquisition time was 14 min, which was necessary to conduct a dynamic curve. A threedimensional T1-weighted sequence, as “intravenous urography”-style reconstruction, was performed at the end of the examination for the assessment of the urinary tract and any increase of the hydronephrosis after furosemide. Split renal function (SRF) was evaluated on the upper and the lower pole on dynamic study, with renal voiding observed in each pole. SRF was compared with the global function. The calculation of the SRF was conducted using the area under the curve method or with the RutlandePatlak method. A pole was considered poorly functional if the value was <5% of the global function. One pathologist systematically reviewed the histological analysis from the heminephrectomies.
Effectiveness of imagery in the assessment of the severity of histological lesions The histological lesions were classified into five specific categories: chronic interstitial inflammation, interstitial fibrosis, tubular atrophy, glomerulosclerosis, and renal dysplasia. Involvement of the pathological specimen by >25% in one or more of these categories was defined as severe histological lesions. Conversely, an involvement by all categories combined of 25% was defined as moderate histological lesions. The results from the diagnostic imaging, and specifically from the MRI, were compared with the histological findings. The statistical analyses were conducted with IBM SPSS PASW statistics software. The continuous variables were presented with averages SD or median with the 25th and 75th quartile. Qualitative variables were presented as total numbers and percentages. The comparison between two groups for continuous variables was done using Student ttest and qualitative variables were compared using the Chi square test or Fisher’s exact test. The multivariate analysis was conducted using stepwise Cox regression model. The threshold of statistic significance was defined as p 0.05.
Results Thirty-four heminephrectomies (26 girls and eight boys) were performed between 2007 and 2013. Median age at surgery was 15 months (range, 2e213) and the mean age was 33.18 months (SD Z 45.5). Twenty-two children (64.7%) were operated on before the age of 2 years. A duplex system was found in 43 kidneys, 26.5% (n Z 9) of these cases were bilateral. Duplex system was suspected because of pyelectasis (10 mm) on US monitoring (32 weeks gestation) for 24/34 children (70.6%) or followed febrile urinary tract infections in 11 cases (32.4%). For six children (17.6%), incontinence made it possible to identify an ectopic ureter of the upper pole. The duplex system was associated with an ureterocele of the upper pole in nine cases (26.5%) and a lower pole VUR in 16 cases (47.1%). The results from renal US were available for all children included. A severe parenchymal thinning was found in 62.5% (n Z 20) and severe hydronephrosis (SFU grade 4) in 35.3% (n Z 12). Twenty-three (67.6%) DMSA scintigraphies were performed. All of the poles studied were considered poorly functioning. Median dose of radiation was 37 Mbq (range, 19e93). MRI was performed on 16 patients (13 girls and three boys) with a median age of 13 months (range, 1e192), with general anesthesia for six (17% of cases). In five cases, the functional analysis could not be performed because of it was impossible to have venous access. Therefore, we recorded five cases of MRI with morphological evaluation and 11 cases of MRU with morphological and functional evaluation. Of the 16 MRIs reviewed, there was cortical thinning in 43.8% (n Z 7) and a dysplastic aspect in 43.8% (n Z 7). A dilatation of the system was found in 68.8% (n Z 11) with a median size of 16 mm (range, 3e57). MRU demonstrated ectopic extravesical ureters, with posterior uretral (n Z 2) or vaginal insertion (n Z 2). It identified ectopic ureteric insertion in all cases (the two other children did not undergo an MRI). Of the 11 dynamic sequences available, a flaw on the
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enhancement of the renal parenchyma was found in 90.9% (n Z 10). Nine poles (81.8%) had SRF <5% and two poles had a SRF >5% (10% and 12% of global function). Surgery was indicated for all the children. An upper pole nephrectomy (UPN) was performed on 27 children (79.4%) and a lower pole nephrectomy (LPN) on seven (20.6%). The procedure was performed by retroperitoneal (n Z 12; 35%) or posterior lumbar approach (n Z 22; 64.7%) according the standard practice in the center. One child underwent a UPN at 33 months as a secondary procedure within 15 months of the initial surgery, after endoscopic incision of the ureterocele. None of the children initially underwent a ureteral reimplantation. No minimal lesions were found in the histological results. Severe histological lesions were identified in 26 specimens (76.5%) and moderate lesions were observed in eight (23.5%). Chronic interstitial inflammation (n Z 25), interstitial fibrosis (n Z 18), and tubular atrophy (n Z 20) were noted in almost every specimen, and were graded severe in 72%, 89% and 90%, respectively. Dysplasia was absent in 27 (80%) of samples, but severe in 85.7%. Of the 27 UPN (79.4%) for duplex systems, tubular atrophy and glomerulosclerosis were significantly associated (p Z 0.05) with ureterocele (n Z 9) and ureteral ectopia (n Z 6) respectively. Severe chronic interstitial inflammation was significantly associated (p Z 0.05) with LPN. The renal US data were compared with the severity of histological lesions. A severe thinning was associated with severe chronic interstitial inflammation (p Z 0.23). The second US variable studied was the degree of hydronephrosis. A significant hydronephrosis (SFU grade > 3) tended to be associated with severe histological lesions (p Z 0.15). A predominance of chronic interstitial inflammation and tubular atrophy was found in children with high SFU hydronephrosis grade (p Z 0.17) (Figs. 1 and 2). Eighteen of the 23 poorly functional poles in DMSA scintigraphy (78.3%) were associated with severe histological lesions (p Z 1), but not to a specific pathological category. The histology was also compared with MRU data. The absence of parenchymal enhancement and/or a severe thinning was significantly associated with interstitial fibrosis (p Z 0.04). A dilatation of the involved pole tended to be associated with chronic interstitial inflammation (p Z 0.063). Poorly functioning poles tended to be associated with severe histological lesions (p Z 0.091), but not to a specific pathological category (Tables 1 and 2). MRU detected damaged poles (presence of irreversible severe histological lesions) with an excellent sensitivity of 100%, a low specificity of 50%, a positive predictive value of 90%, and a poor negative predictive value of 0%. Each MRI variable was independently correlated with severe histological lesions. The association of poor renal function and the absence of enhancement of the renal parenchyma on MRU, severe thinning, and high degree of hydronephrosis on US tended to be predictive factors for severe histological lesions.
Discussion Despite the progress in pediatric imagery, diagnosis, and management, duplex systems remained a challenge for
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A. Faure et al.
Figure 1 Four-month-old girl with prenatal diagnosis of pyelectasis on ultrasound (US) monitoring. Renal US shows a duplicated renal kidney with an upper pole cortical thinning (*) and hydronephrosis. T2-weighted static fluid magnetic resonance urography (MRU) in sagittal plane (c, e) depicts dilated upper moiety and associated ectopic ureter (axial plane, d). T1-weighted gadoliniumenhanced MRU depicts collecting systems on both sides, with a split renal function of the upper pole evaluated at 12% of the global function. Chronic interstitial inflammation lesions were detected on histological analysis from heminephrectomies (hematoxylin and eosin, 100) (g).
clinicians. Heminephrectomy is based on results from standard imagery examinations, the sensitivity and specificity of which is often doubted, specifically for functional evaluation of an obstructed pole. The anatomical assessment of a duplex system with an obstruction of the upper pole or ureteral ectopia requires
multiple imaging modalities. As US is highly accessible, it is the first examination performed but it does not allow to see the path of the ureters. VCUG, renal scintigraphy, and cystoscopy can be performed in addition to US, but they are invasive and use ionizing radiation. The current standard practice for the evaluation of functional consequences of a
Figure 2 Fifteen-month-old with duplex system with upper pole hydronephrosis and severe cortical thinning on renal ultrasound (a). Ureterocele was located intravesically (b, arrow). On T2-weighted magnetic resonance urography (MRU) the dilatation of the upper pole was confirmed (cee). Global kidney destruction was evident without enhancement. T1-weighted gadolinium-enhanced MRU detected duplex system on left side with nonfunctioning dysplasic upper pole (f). Atrophic tubules were replaced by severe interstitial fibrosis (hematoxylin and eosin, 100) (g). Glomerulosclerosis lesion (*) (h).
Effectiveness of imagery in the assessment of the severity of histological lesions
365
Table 1 Analysis of histological lesions from sample tissues from heminephrectomies according to the imagery criteria defined in the study. Note. US Z ultrasound; MRI Z magnetic resonance imaging; SFU Z Society for Fetal Urology; SRF Z split renal function. *p < 0.05. Renal US
SFU hydronephrosis grade >3
17
Severe cortical thinning
9
8
6
10
6
5
7
3
2
2
7
16
SRF <5%
14
9
6
MRI
Dysplasic aspect
3
5
Absence of enhancement
4
8
7
Severe cortical thinning
7
5
4
3
1
4 1
Chronic interstitial inflammation interstitial fibrosis Tubular atrophy Glomerulosclerosis Dysplasia
dilated, but functional, moieties (T1 sequences with gadolinium) and to visualize the lower poles, often poorly evaluated because of the dilatation of the upper system [16]. In our study, we were able to demonstrate, for the first time, that the poorly functioning pole in MRU corresponded to 100% of severe histological lesions. In the case of residual renal function in the upper pole (>10% for two patients, 12.5%), there were only moderate lesions. The main goal of this study was to obtain significant sensitive imaging with non-invasive techniques to detect severe histological lesions. The sensitivity of MRU was excellent (90%) for the
urinary obstruction is dynamic renal scintigraphy, but it has an insufficient spatial resolution. Our study confirmed the feasibility of MRU, even in neonates and infants. MRU has been successfully used for the anatomical exploration of duplex systems [3] and has made it possible to obtain precise data on ureteral insertion and the degree of obstruction [4,11e14] without sedation during the first year of life (100% of ureteral ectopia were detected). As Staatz et al. [15] reported, when compared with DMSA scintigraphy, MRU had the advantage of providing functional and morphological information on the involved pole. It also made it possible to detect
Table 2 Severity of histological lesions from heminephrectomies according to imagery criteria defined in the study. Note. US Z ultrasound; MRI Z magnetic resonance imaging; SFU Z Society for Fetal Urology; SRF Z split renal function. *p < 0.05. Renal US
SFU hydronephrosis grade >3
14
4
Severe cortical thinning
6
SRF <5%
MRI
Dysplasic aspect
14
9
6
1
Absence of enhancement
10
Severe cortical thinning
7
Moderate histological lesions Severe histological lesions
366 positive diagnosis of a damaged pole and for the topography of ectopic ureteral insertion in a duplex system. Our results corroborated current results from the literature. Bolduc et al. [17] reported that a severe parenchymal thinning (of undefined size) on US was significantly associated with severe histological lesions. After comparing the US data with the SRF obtained with MRU, US made it possible to predict histological lesions and the loss of cortical function of the affected pole. All poles evaluated with DMSA scintigraphy were poorly functional. In five cases (21.3%), moderate histological lesions were identified. Sensitivity and specificity were excellent in detecting renal damage, according to the results from the literature [17,18]. Nevertheless, DMSA scintigraphy is pertinent in the evaluation of renal scars [19] and unreliable in evaluating split renal function. No correlative analysis was conducted with the scintigraphy examinations requested and histological lesions because no dynamic scintigraphy was performed to evaluate the renal function and excretion of the affected poles. Stokland et al. [20] underline the problems in the interpretation of DMSA scintigraphy for diagnosis of the renal function in dilated duplex system. DMSA scintigraphy was not a pertinent examination for the evaluation relative function in a unilateral duplication with risk of overdiagnosed renal damage. Specific pathological categories of lesions were not significantly associated with poorly functioning poles in MRU. Contrary to results from the literature, no severe dysplasia lesions were observed in the upper pole associated with a ureterocele [17,21,22], possibly owing to the small sample size. The comparison between MRU data and the histological findings confirmed that MRU was a reliable examination to determine the histological nature of the renal parenchyma for patients without chronic infection. Chronic infection can complicate histological analysis. MRU should be proposed as a standard of practice for the anatomical and functional exploration of duplex systems in children <6 months because it is accurate, non-invasive, and does not require general anesthesia [23,24]. We found that it was possible to predict the severity of histological lesions with preoperative MRU. In this retrospective study, we recorded 160 cases of duplication in our institutions and only 34 children (21.2%) underwent a heminephrectomy based on results of preoperative imagery. However, this small sample group was representative of the activity in three referral centers over 6 years. It would have been interesting to analyze the histological results of poorly or non-functioning poles that were left in place in order to answer the question if they should be removed. MRU is considered an expensive technique. It has been shown that performing functional MRU instead of the reference strategy (combined dynamic renal scintigraphy with morphological MRI) for the evaluation of urinary obstruction would reduce the average cost per patient by V200 (V100 additional cost for sedation). Theoretically, MRU may reduce overall healthcare expenses.
Conclusion In complicated duplex kidneys the aim of imaging is to visualize the anatomy and determine the precise the
A. Faure et al. function of the two moieties. MRI can perform this dual analysis with one quality diagnostic examination. MRI made it possible to predict severe histological lesions in the affected pole. In our practice, MRI can be a useful adjunct for the diagnosis of duplex system with suspected ectopic ureter, when ordinary imaging techniques (e.g., US and scintigraphy) are inconclusive, especially in children younger than 6 months.
Conflict of interest None.
Funding None.
Acknowledgments Thanks to A.D. Loundou for the statistical analysis.
References [1] Campbell MF. Surgical treatment of anomalies of upper urinary tract in children. J Am Med Assoc 1936;106:193e6. [2] Nation EF. Duplication of the kidney and ureter: a statistical study of 230 new cases. J Urol 1944;51:456e65. [3] Borthne A, Nordshus T, Reiseter T, Geitung JT, Gjesdal KI, Babovic A, et al. MR urography: the future gold standard in pediatric urogenital imaging? Pediatr Radiol 1999;29:694e701. [4] Borthne A, Pierre-Jerome C, Nordshus T, Reiseter T. MR urography in children: current status and future development. Eur Radiol 2000;10:503e11. [5] Avni FE, Nicaise N, Hall M, Janssens F, Collier F, Matos C, et al. The role of MR imaging for the assessment of complicated duplex kidneys in children: preliminary report. Pediatr Radiol 2001;31:215e23. [6] Knesplova L, Krestin GP. Magnetic resonance in the assessment of renal function. Eur Radiol 1998;8:201e11. [7] Frank JA, Choyke PL, Austin HA, Girton ME. Functional MR of the kidney. Magn Reson Med 1991;22:319e23. [8] Benett HF, Li D. MR imaging of renal function. Magn Reson Imaging Clin N Am 1997;5:107e26. [9] Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Mobius TE. International system of radiographic grading of vesicoureteric reflux. International reflux study in children. Pediatr Radiol 1985;15:105e9. [10] Fernbach SK, Maizels M, Conway JJ. Ultrasound grading of hydronephrosis: introduction to the system used by the Society for Fetal Urology. Pediatr Radiol 1993;23:478e80. [11] Vegar-Zubovic S, Kristic S, Lincender L. Magnetic resonance urography in children e when and why? Radiol Oncol 2011;45: 174e9. [12] Reuther G, Kiefer B, Wandl E. Visualization of urinary tract dilatation: the value of single shot MR urography. Eur Radiol 1997;7:1276e81. [13] Avni FE, Matos C, Rypens F, Schulman CC. Ectopic vaginal insertion of an upper pole ureter: demonstration by special sequences of magnetic resonance imaging. J Urol 1997;158: 1931e2. [14] Rothpearl A, Frager D, Subramanian A, Bashist B, Baer J, Kay C, et al. MR urography: technique and application. Radiology 1995;194:125e30.
Effectiveness of imagery in the assessment of the severity of histological lesions [15] Staatz G, Nolte-Ernsting CCA, Adam GB, Hubner D, Rohrmann D, Stollbrink C, et al. Feasibility and utility of respiratory-gated, gadolinium-enhanced T1 weighted magnetic resonance urography in children. Invest Radiol 2000;35:504e12. [16] Perez-Brayfield MR, Kirsch AJ, Jones RA, Grattan-Smith JD. A prospective study comparing ultrasound, nuclear scintigraphy and dynamic contrast-enhanced magnetic resonance imaging in the evaluation of hydronephrosis. J Urol 2004;170:1330e4. [17] Bolduc S, Upadhyay J, Restrepo R, Sherman C, Farhat W, Ba ¨gli DJ, et al. The predictive value of diagnostic imaging for histological lesions of the upper poles in duplex systems with ureteroceles. BJU Int 2003;91:678e82. [18] Coplen DE, Duckett JW. The modern aprroach to ureteroceles. J Urol 1995;153:166e71. [19] Rushton HG, Majd M. Dimercaptosuccinic acid renal scintigraphy for the evaluation of pyelonephritis and scarring: a review of experimental and clinical studies. J Urol 1992;148: 1726e32.
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[20] Stokland E, Jodal U, Sixt R, Swerkersson S, Hansson S. Uncomplicated duplex kidney and DMSA scintigraphy in children with urinary tract infection. Pediatr Radiol 2007;37:826e8. [21] Abel C, Lendon M, Gough DC. Histology of the upper pole in complete urinary duplication-does it affect surgical management? Br J Urol 1997;80:663e5. [22] Bolduc S, Upadhyay J, Sherman C, Farhat W, Ba ¨gli DJ, McLorie GA, et al. Histology of upper pole is unaffected by prenatal diagnosis in duplex system ureteroceles. J Urol 2002; 168:1123e6. [23] Ehammer T, Riccabona M, Maier E. High resolution MR for evaluation of lower urogenital tract malformations in infants and children: feasibility and preliminary experiences. Eur J Radiol 2011;78:388e93. [24] Riccabona M, Simbrunner J, Ring E, Ruppert-Kohlmayr A, Ebner F, Fotter R. Feasibility of MR urography in neonates and infants with anomalies of the upper urinary tract. Eur Radiol 2002;12:1442e50.
Value of diagnosis imaging in the evaluation of the severity of histological lesions in duplex systems Alice Faure a,*, Thierry Merrot a, Quentin Sala b, Kathia Chaumoitre c, Jean-Michel Guys d, Brigitte Bourliere-Najean e, Julia Torrents f, Olivier Mundler b, Eric Lechevallier g, Pierre Alessandrini a a
Department of Pediatric Surgery, Hospital Nord, APHM, Aix-Marseille University, Chemin des Bourrely, Marseille 13015, France b Department of Nuclear Medicine, Hospital Timone, APHM, Aix-Marseille University, Marseille, France c Department of Medical Imaging, Hospital Nord, APHM, Aix-Marseille University, Marseille, France d Department of Pediatric Surgery, Hospital Timone, APHM, Aix-Marseille University, Marseille, France e Department of Pediatric Radiology, Hospital Timone, APHM, Aix-Marseille University, Marseille, France f Department of Pathology, Hospital Timone, APHM, Aix-Marseille University, Marseille, France g Department of Urology, Hospital Conception, APHM, Aix-Marseille University, Marseille, France Received 29 May 2013; accepted 5 October 2013 Available online 5 November 2013
KEYWORDS Pole nephrectomy; Duplex systems; Magnetic resonance urography; Ureterocele; Split renal function
Abstract Objective: In order to determine the effectiveness of imagery in the assessment of the severity of histological lesions in duplex systems in children we compared histology results from heminephrectomies with diagnosis imaging findings [renal ultrasound (US), scintigraphy, unenhanced and contrast-enhanced magnetic resonance imagery (MRI)]. Materials and methods: Between 2007 and 2013, 34 children with duplex system underwent surgery. The results from US (n Z 34), dimer captosuccinic acid scintigraphy (n Z 23) and MRI (n Z 16) were compared with histological data. Five histological lesions were found (chronic interstitial inflammation, interstitial fibrosis, tubular atrophy, glomerulosclerosis and dysplasia) and categorized as severe (>25%) or moderate (25%). Results: Severe histological lesions were found in 76.5% and moderate lesions in 23.5%. Radiological features were compared with histological results. In US, severe parenchymal thinning was associated with chronic interstitial inflammatory. The absence of parenchymal enhancement and/or severe cortical thinning in MR urography (MRU) was significantly
*Corresponding author. Tel.: þ33 4 91 96 86 36; fax: þ33 4 91 96 86 38. E-mail address: [email protected] (A. Faure). 1477-5131/$36 ª 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpurol.2013.10.009
362
A. Faure et al. associated with interstitial fibrosis. All poorly functioning poles were associated with severe histological lesions (p Z 0.091), but not to a specific category of lesions. Conclusions: MRI sensibility was excellent (90%) in the diagnosis of poorly functioning pole. Severe thinning on US and minimal pole function on MRU can be used to predict the severity of histological lesions. ª 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Introduction Duplex systems are one of the most common anomalies of the upper urinary tract collecting system in children (0.5e1.25% on a series of autopsies) [1,2]. A vesicoureteral reflux (VUR) in the lower pole of a duplex system, or an obstruction of the upper urinary tract by a ureterocele or by an ectopic ureter can be responsible for loss of cortical function associated with significant parenchymal lesions. Current imagery techniques make it possible to characterize the duplex system and to help therapeutic decisions. A heminephrectomy is indicated for a poorly functioning pole associated with upper urinary tract infections or for incontinence due to ectopic ureter. Magnetic resonance urography (MRU) has been successfully used for the evaluation of pediatric urinary tract disease and is the most accurate test for the diagnosis of complications associated with duplex systems [3,4]. It is possible to study the anatomy and function of the affected renal parenchyma with MRU [5]. Unlike renal scintigraphy [dimer captosuccinic acid (DMSA) and mercaptoacetyltriglycine (MAG-3)], with MRU it is possible to identify an obstructive syndrome and/or an ectopic ureter including in renal units with poorly function without using ionizing radiation [6e8]. There are no studies in the literature that compare functional MRU results with histological lesions from pathologic poles in duplex systems. The objective of this study was to compare diagnosis imaging and the results with histological findings from heminephrectomy in order to determine the role of MRU in the evaluation of the severity of histological lesions in duplex systems.
Materials and methods Between 2007 and 2013, data were collected from three referral centers concerning 34 children who underwent heminephrectomies for a non-functioning pole among 160 duplex systems recorded in total. An analysis comparing unenhanced and contrast-enhanced magnetic resonance imagery (MRI) and histological findings was conducted using clinical data and the medical imagery. Two pediatric radiologists, unaware of the clinical history, surgical procedures and histological lesions reviewed preoperative imagery. The indications for surgery were a poorly functioning pole and urinary tract infections and/or incontinence in the case of extravesical ectopic ureter. All children aged between 0 and 18 years old who underwent a heminephrectomy were included. The exclusion criteria were incomplete medical files, bifid system, duplex
system that had been operated on but without heminephrectomy (ureteral reimplantation of both ureters, uretero-ureterostomy, pyeloplasty for ureteropelvic junction obstruction, nephrectomy) and duplex system that had been closely monitored. A renal ultrasound (US) was systematically performed for the preoperative evaluation and was sometimes associated with a voiding cystourethrography (VCUG) in order to search for VUR (grade IeV according to international recommendations) [9]. Parenchymal renal thinning was evaluated and categorized as moderate (cortical thickness > 1.5 mm) or severe (cortical thickness < 1.5 mm). The aspect and degree of hydronephrosis was also examined and evaluated according to the Society for Fetal Urology (SFU) grading system [10]. Static renal scintigraphy with 99 m technetium (Tc) DMSA was performed on 13 children (38%) with a dose of 1 MBq/kg. A local, or absence of, uptake was considered abnormal and indicated a restricted activity to the pole. A poorly functioning pole was arbitrarily defined as <5% of the global function. In three centers, 16 children (47%) underwent a MRI using a Tesla 1.5 MRI with sedation adapted to age in order to limit movement-related artifacts. Infants younger than 6 months were not sedateddadequate immobilization was obtained after feeding. Children younger than 5 years were placed in supine position on a plexiglas plate with restraining straps. Some examinations were performed with general anesthesia. The exploratory protocol included morphological T2weighted sequences in three planes in thin slices (4e5 mm thickness) then in thick-slice heavily T2-weighted sequences for anatomical display or fluid-filled structures. Functional examination was performed using contrastenhanced T1-weighted sequences. Gadolinium (0.1 ml/kg) was injected at the same time as furosemide (0.5 mg/kg, maximum 20 mg). The acquisition time was 14 min, which was necessary to conduct a dynamic curve. A threedimensional T1-weighted sequence, as “intravenous urography”-style reconstruction, was performed at the end of the examination for the assessment of the urinary tract and any increase of the hydronephrosis after furosemide. Split renal function (SRF) was evaluated on the upper and the lower pole on dynamic study, with renal voiding observed in each pole. SRF was compared with the global function. The calculation of the SRF was conducted using the area under the curve method or with the RutlandePatlak method. A pole was considered poorly functional if the value was <5% of the global function. One pathologist systematically reviewed the histological analysis from the heminephrectomies.
Effectiveness of imagery in the assessment of the severity of histological lesions The histological lesions were classified into five specific categories: chronic interstitial inflammation, interstitial fibrosis, tubular atrophy, glomerulosclerosis, and renal dysplasia. Involvement of the pathological specimen by >25% in one or more of these categories was defined as severe histological lesions. Conversely, an involvement by all categories combined of 25% was defined as moderate histological lesions. The results from the diagnostic imaging, and specifically from the MRI, were compared with the histological findings. The statistical analyses were conducted with IBM SPSS PASW statistics software. The continuous variables were presented with averages SD or median with the 25th and 75th quartile. Qualitative variables were presented as total numbers and percentages. The comparison between two groups for continuous variables was done using Student ttest and qualitative variables were compared using the Chi square test or Fisher’s exact test. The multivariate analysis was conducted using stepwise Cox regression model. The threshold of statistic significance was defined as p 0.05.
Results Thirty-four heminephrectomies (26 girls and eight boys) were performed between 2007 and 2013. Median age at surgery was 15 months (range, 2e213) and the mean age was 33.18 months (SD Z 45.5). Twenty-two children (64.7%) were operated on before the age of 2 years. A duplex system was found in 43 kidneys, 26.5% (n Z 9) of these cases were bilateral. Duplex system was suspected because of pyelectasis (10 mm) on US monitoring (32 weeks gestation) for 24/34 children (70.6%) or followed febrile urinary tract infections in 11 cases (32.4%). For six children (17.6%), incontinence made it possible to identify an ectopic ureter of the upper pole. The duplex system was associated with an ureterocele of the upper pole in nine cases (26.5%) and a lower pole VUR in 16 cases (47.1%). The results from renal US were available for all children included. A severe parenchymal thinning was found in 62.5% (n Z 20) and severe hydronephrosis (SFU grade 4) in 35.3% (n Z 12). Twenty-three (67.6%) DMSA scintigraphies were performed. All of the poles studied were considered poorly functioning. Median dose of radiation was 37 Mbq (range, 19e93). MRI was performed on 16 patients (13 girls and three boys) with a median age of 13 months (range, 1e192), with general anesthesia for six (17% of cases). In five cases, the functional analysis could not be performed because of it was impossible to have venous access. Therefore, we recorded five cases of MRI with morphological evaluation and 11 cases of MRU with morphological and functional evaluation. Of the 16 MRIs reviewed, there was cortical thinning in 43.8% (n Z 7) and a dysplastic aspect in 43.8% (n Z 7). A dilatation of the system was found in 68.8% (n Z 11) with a median size of 16 mm (range, 3e57). MRU demonstrated ectopic extravesical ureters, with posterior uretral (n Z 2) or vaginal insertion (n Z 2). It identified ectopic ureteric insertion in all cases (the two other children did not undergo an MRI). Of the 11 dynamic sequences available, a flaw on the
363
enhancement of the renal parenchyma was found in 90.9% (n Z 10). Nine poles (81.8%) had SRF <5% and two poles had a SRF >5% (10% and 12% of global function). Surgery was indicated for all the children. An upper pole nephrectomy (UPN) was performed on 27 children (79.4%) and a lower pole nephrectomy (LPN) on seven (20.6%). The procedure was performed by retroperitoneal (n Z 12; 35%) or posterior lumbar approach (n Z 22; 64.7%) according the standard practice in the center. One child underwent a UPN at 33 months as a secondary procedure within 15 months of the initial surgery, after endoscopic incision of the ureterocele. None of the children initially underwent a ureteral reimplantation. No minimal lesions were found in the histological results. Severe histological lesions were identified in 26 specimens (76.5%) and moderate lesions were observed in eight (23.5%). Chronic interstitial inflammation (n Z 25), interstitial fibrosis (n Z 18), and tubular atrophy (n Z 20) were noted in almost every specimen, and were graded severe in 72%, 89% and 90%, respectively. Dysplasia was absent in 27 (80%) of samples, but severe in 85.7%. Of the 27 UPN (79.4%) for duplex systems, tubular atrophy and glomerulosclerosis were significantly associated (p Z 0.05) with ureterocele (n Z 9) and ureteral ectopia (n Z 6) respectively. Severe chronic interstitial inflammation was significantly associated (p Z 0.05) with LPN. The renal US data were compared with the severity of histological lesions. A severe thinning was associated with severe chronic interstitial inflammation (p Z 0.23). The second US variable studied was the degree of hydronephrosis. A significant hydronephrosis (SFU grade > 3) tended to be associated with severe histological lesions (p Z 0.15). A predominance of chronic interstitial inflammation and tubular atrophy was found in children with high SFU hydronephrosis grade (p Z 0.17) (Figs. 1 and 2). Eighteen of the 23 poorly functional poles in DMSA scintigraphy (78.3%) were associated with severe histological lesions (p Z 1), but not to a specific pathological category. The histology was also compared with MRU data. The absence of parenchymal enhancement and/or a severe thinning was significantly associated with interstitial fibrosis (p Z 0.04). A dilatation of the involved pole tended to be associated with chronic interstitial inflammation (p Z 0.063). Poorly functioning poles tended to be associated with severe histological lesions (p Z 0.091), but not to a specific pathological category (Tables 1 and 2). MRU detected damaged poles (presence of irreversible severe histological lesions) with an excellent sensitivity of 100%, a low specificity of 50%, a positive predictive value of 90%, and a poor negative predictive value of 0%. Each MRI variable was independently correlated with severe histological lesions. The association of poor renal function and the absence of enhancement of the renal parenchyma on MRU, severe thinning, and high degree of hydronephrosis on US tended to be predictive factors for severe histological lesions.
Discussion Despite the progress in pediatric imagery, diagnosis, and management, duplex systems remained a challenge for
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A. Faure et al.
Figure 1 Four-month-old girl with prenatal diagnosis of pyelectasis on ultrasound (US) monitoring. Renal US shows a duplicated renal kidney with an upper pole cortical thinning (*) and hydronephrosis. T2-weighted static fluid magnetic resonance urography (MRU) in sagittal plane (c, e) depicts dilated upper moiety and associated ectopic ureter (axial plane, d). T1-weighted gadoliniumenhanced MRU depicts collecting systems on both sides, with a split renal function of the upper pole evaluated at 12% of the global function. Chronic interstitial inflammation lesions were detected on histological analysis from heminephrectomies (hematoxylin and eosin, 100) (g).
clinicians. Heminephrectomy is based on results from standard imagery examinations, the sensitivity and specificity of which is often doubted, specifically for functional evaluation of an obstructed pole. The anatomical assessment of a duplex system with an obstruction of the upper pole or ureteral ectopia requires
multiple imaging modalities. As US is highly accessible, it is the first examination performed but it does not allow to see the path of the ureters. VCUG, renal scintigraphy, and cystoscopy can be performed in addition to US, but they are invasive and use ionizing radiation. The current standard practice for the evaluation of functional consequences of a
Figure 2 Fifteen-month-old with duplex system with upper pole hydronephrosis and severe cortical thinning on renal ultrasound (a). Ureterocele was located intravesically (b, arrow). On T2-weighted magnetic resonance urography (MRU) the dilatation of the upper pole was confirmed (cee). Global kidney destruction was evident without enhancement. T1-weighted gadolinium-enhanced MRU detected duplex system on left side with nonfunctioning dysplasic upper pole (f). Atrophic tubules were replaced by severe interstitial fibrosis (hematoxylin and eosin, 100) (g). Glomerulosclerosis lesion (*) (h).
Effectiveness of imagery in the assessment of the severity of histological lesions
365
Table 1 Analysis of histological lesions from sample tissues from heminephrectomies according to the imagery criteria defined in the study. Note. US Z ultrasound; MRI Z magnetic resonance imaging; SFU Z Society for Fetal Urology; SRF Z split renal function. *p < 0.05. Renal US
SFU hydronephrosis grade >3
17
Severe cortical thinning
9
8
6
10
6
5
7
3
2
2
7
16
SRF <5%
14
9
6
MRI
Dysplasic aspect
3
5
Absence of enhancement
4
8
7
Severe cortical thinning
7
5
4
3
1
4 1
Chronic interstitial inflammation interstitial fibrosis Tubular atrophy Glomerulosclerosis Dysplasia
dilated, but functional, moieties (T1 sequences with gadolinium) and to visualize the lower poles, often poorly evaluated because of the dilatation of the upper system [16]. In our study, we were able to demonstrate, for the first time, that the poorly functioning pole in MRU corresponded to 100% of severe histological lesions. In the case of residual renal function in the upper pole (>10% for two patients, 12.5%), there were only moderate lesions. The main goal of this study was to obtain significant sensitive imaging with non-invasive techniques to detect severe histological lesions. The sensitivity of MRU was excellent (90%) for the
urinary obstruction is dynamic renal scintigraphy, but it has an insufficient spatial resolution. Our study confirmed the feasibility of MRU, even in neonates and infants. MRU has been successfully used for the anatomical exploration of duplex systems [3] and has made it possible to obtain precise data on ureteral insertion and the degree of obstruction [4,11e14] without sedation during the first year of life (100% of ureteral ectopia were detected). As Staatz et al. [15] reported, when compared with DMSA scintigraphy, MRU had the advantage of providing functional and morphological information on the involved pole. It also made it possible to detect
Table 2 Severity of histological lesions from heminephrectomies according to imagery criteria defined in the study. Note. US Z ultrasound; MRI Z magnetic resonance imaging; SFU Z Society for Fetal Urology; SRF Z split renal function. *p < 0.05. Renal US
SFU hydronephrosis grade >3
14
4
Severe cortical thinning
6
SRF <5%
MRI
Dysplasic aspect
14
9
6
1
Absence of enhancement
10
Severe cortical thinning
7
Moderate histological lesions Severe histological lesions
366 positive diagnosis of a damaged pole and for the topography of ectopic ureteral insertion in a duplex system. Our results corroborated current results from the literature. Bolduc et al. [17] reported that a severe parenchymal thinning (of undefined size) on US was significantly associated with severe histological lesions. After comparing the US data with the SRF obtained with MRU, US made it possible to predict histological lesions and the loss of cortical function of the affected pole. All poles evaluated with DMSA scintigraphy were poorly functional. In five cases (21.3%), moderate histological lesions were identified. Sensitivity and specificity were excellent in detecting renal damage, according to the results from the literature [17,18]. Nevertheless, DMSA scintigraphy is pertinent in the evaluation of renal scars [19] and unreliable in evaluating split renal function. No correlative analysis was conducted with the scintigraphy examinations requested and histological lesions because no dynamic scintigraphy was performed to evaluate the renal function and excretion of the affected poles. Stokland et al. [20] underline the problems in the interpretation of DMSA scintigraphy for diagnosis of the renal function in dilated duplex system. DMSA scintigraphy was not a pertinent examination for the evaluation relative function in a unilateral duplication with risk of overdiagnosed renal damage. Specific pathological categories of lesions were not significantly associated with poorly functioning poles in MRU. Contrary to results from the literature, no severe dysplasia lesions were observed in the upper pole associated with a ureterocele [17,21,22], possibly owing to the small sample size. The comparison between MRU data and the histological findings confirmed that MRU was a reliable examination to determine the histological nature of the renal parenchyma for patients without chronic infection. Chronic infection can complicate histological analysis. MRU should be proposed as a standard of practice for the anatomical and functional exploration of duplex systems in children <6 months because it is accurate, non-invasive, and does not require general anesthesia [23,24]. We found that it was possible to predict the severity of histological lesions with preoperative MRU. In this retrospective study, we recorded 160 cases of duplication in our institutions and only 34 children (21.2%) underwent a heminephrectomy based on results of preoperative imagery. However, this small sample group was representative of the activity in three referral centers over 6 years. It would have been interesting to analyze the histological results of poorly or non-functioning poles that were left in place in order to answer the question if they should be removed. MRU is considered an expensive technique. It has been shown that performing functional MRU instead of the reference strategy (combined dynamic renal scintigraphy with morphological MRI) for the evaluation of urinary obstruction would reduce the average cost per patient by V200 (V100 additional cost for sedation). Theoretically, MRU may reduce overall healthcare expenses.
Conclusion In complicated duplex kidneys the aim of imaging is to visualize the anatomy and determine the precise the
A. Faure et al. function of the two moieties. MRI can perform this dual analysis with one quality diagnostic examination. MRI made it possible to predict severe histological lesions in the affected pole. In our practice, MRI can be a useful adjunct for the diagnosis of duplex system with suspected ectopic ureter, when ordinary imaging techniques (e.g., US and scintigraphy) are inconclusive, especially in children younger than 6 months.
Conflict of interest None.
Funding None.
Acknowledgments Thanks to A.D. Loundou for the statistical analysis.
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