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Insights into the Pathogenesis and Natural History of Fetuses with Renal Pelvis Dilatation
European Urology
European Urology 48 (2005) 207–214
ReviewPaediatric and Reconstructive Urology
Insights into the Pathogenesis and Natural History of Fetuses with Renal Pelvis Dilatation Khalid ismailia,*, Michelle Halla, Amy Piepszb, Marc Alexanderc, Claude Schulmand, Fred E. Avnie a
Department of Perinatal and Pediatric Nephrology, Hoˆpital Universitaire des Enfants – Reine Fabiola, 15, Avenue J.J. CROCQ, 1020–Brussels, Belgium b Department of Nuclear Medicine. Centre Hospitalier Universitaire St. Pierre c Department of Pediatrics. Centre Hospitalier Etterbeek-Ixelles d Department of Urology, Hoˆpital Erasme e Department of Radiology, Hoˆpital Erasme, Universite´ Libre de Bruxelles (ULB), Brussels, Belgium Accepted 15 February 2005 Available online 16 March 2005
Abstract Fetal renal pelvis dilatation is a frequent abnormality that has been observed in 4.5% of pregnancies. The majority of these cases have a tendency to resolve during infancy. Nevertheless, fetal renal pelvis dilatation may be due to significant structural abnormalities such as pelvi-ureteric junction stenosis or vesico-ureteral reflux that may adversely affect renal function or cause urinary infection or sepsis. This review article aims to summarize the data regarding fetal renal pelvis dilatation and to analyze controversial attitudes in the light of the various lines of practice, and to present rational antenatal and postnatal investigation strategy. # 2005 Elsevier B.V. All rights reserved. Keywords: Vesico-ureteral reflux; Fetal hydronephrosis; Urinary tract pathology; Ultrasonography
1. Introduction The introduction of routine fetal ultrasonographic examination has improved the detection rate of fetal anomalies, while the technical developments of ultrasound (US) equipment have increased diagnostic accuracy. This has led to the discovery of many fetal anomalies, and among them, upper urinary tract dilatation (Fig. 1) represents one of the largest groups amenable to neonatal management [1]. This finding, which may be recognized from the beginning of the second trimester of pregnancy, was assumed in early reports to be physiologic or nonobstructive, and therefore follow-up was not always obtained after the initial Abbreviations: MRI, Magnetic resonance imaging; US, Ultrasound; VCUG, Voiding cystourethrography; VUR, Vesico-ureteral reflux. * Corresponding author. Tel. +32 2 4772152; Fax: +32 2 4772154. E-mail address: [email protected] (K. ismaili).
identification [2,3]. Nevertheless, renal pelvic dilatation can be an early sonographic sign of fetal hydronephrosis [4], or as a marker of other abnormalities such as renal duplication or vesico-ureteral reflux (VUR) which cannot be easily identified by US during pregnancy [5]. Therefore, the patient is now presenting to the urologist or pediatric nephrologist before the baby is even born, with a presumptive diagnosis rather than a symptom. The detection of any fetal abnormality, including renal pelvis dilatation, generates considerable parental concern. Nevertheless, the expecting mother should be adequately informed of renal pelvis dilatation and its clinical significance [6]. Therefore, it is essential to have a clear idea of the range of potential differential diagnoses and likely outcome in order to make rational decisions concerning the treatment of these babies. There have been numerous articles discussing the significance of fetal renal pelvis dilatation as indicator
0302-2838/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.02.014
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Fig. 1. Prenatal ultrasound showing transverse view of a right renal pelvis dilatation. K (kidney), Sp (spine), DR (right), D (diameter).
of certain developmental abnormalities in the urinary tract. However, the long-term clinical implications of this condition have rarely been established in large and prospective cohort studies [7,8].
2. Definition and incidence Fetal renal pelvis dilatation is a frequent abnormality that has been observed in 4.5% of pregnancies [9]. Nevertheless, some controversy exists in the literature regarding the definition and significance of this finding. Pyelectasis is defined as dilatation of the renal pelvis whereas pyelocaliectasis and hydronephrosis include dilatation of calyces. Practically, the three terms are interchanged and all used as descriptions of a dilated renal collecting system, regardless of its etiology [1]. The majority of authors use the antero-posterior renal pelvis diameter system for classification of fetal renal pelvis dilatation. The Society for Fetal Urology (SFU) system [4] has another classification based upon calyceal dilatation rather than renal pelvic dilatation, but it is deemed to be less easily reproducible [10]. The first measurements of the antero-posterior fetal renal pelvis diameter in the 80’s suggested that a threshold value of 10 mm indicated the need for a full investigation of the urinary tract in early postnatal life [11]. The routine use of prenatal US with sufficiently sophisticated machines allowed the detection of smaller dilatations. In the early 90’s, the analysis of Corteville’s retrospective study [12] has demonstrated that the use of pyelectasis threshold values diameters of 4 mm in the second trimester and 7 mm in the third trimester of pregnancy permitted a more effective detection of urinary tract anomalies. Yet, more recent studies have
shown that the incidence of fetal pyelectasis is much higher when such small threshold diameters are used (Table 1). Very few studies have attempted to correct cut-off values for gestational age [5]. A notable exception is a recent prospective study that assessed the significance of renal pelvic diameters at different stages in gestation by correlating 16,929 measurements with the postnatal outcome [9]. This study concluded that 76% of dilatations, mostly between 4 and 7 mm, had been detected in the second trimester. In this series, only 12% of kidneys turned out to be linked to a significant nephrourological malformation, mostly VUR, when the antero-posterior dimension remained less than 7 mm in the third trimester. Simeoni et al. [17] have suggested that only pelvic dilatation greater than 10 mm after 28 weeks of gestation necessitates postnatal investigation. Other authors [9,18] did not confirm this statement. The proportion of abnormal kidneys diagnosed after birth seems significantly higher when using a third-trimester cut-off point of antero-posterior fetal renal pelvis diameter of 7 mm in comparison with a cut-off point of 10 mm. Besides the degree of fetal renal collecting system dilatation, other prognostic predictors of outcome include [1]: 1. 2. 3. 4.
The involvement of both kidneys. The presence of coexisting renal dysplasia. A decreased amount of amniotic fluid. Coexisting associated anomalies, which may eventually lead to karyotyping. 5. Significant modification of fetal urine biochemical markers that may have some role in predicting poor renal function postnatally. High sodium (>100 mEq/l after 20 weeks) [19], high calcium (>1.2 mmol/l) [20] and high b2-microglobulin (>2 mg/l) [19]. Nevertheless, the accuracy of these parameters is far from perfect [21]. 6. Fetal blood sampling probably poses greater risks than urine sampling, but allows measurement of better index of fetal glomerular filtration rate [21]. Serum b2-microglobulin could be of clinical interest only when extreme values are found (<3.5 mg/l good outcome; > 5 mg/l poor outcome) [22].
3. Pathophysiology There are several theories that account for the visibility of the renal pelvis during pregnancy. The distension of the urinary collecting system may be a
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Table 1 Definition and reported incidence of isolated renal pelvis dilatation Authors
Number of fetuses screened
Morin et al. [13]
5900
Langer et al. [14]
2170
Persutte et al. [15] Thompson and Thilaganathan [16] Ismaili et al. [9]
5529 10971 5643
dynamic and physiologic process [23]. Recently, Persutte et al. found the size of the fetal renal collecting system to be highly variable over the course of a 2-hour period [24]. Nevertheless, pyelectasis may be due to significant structural abnormalities that may adversely affect renal function or cause urinary infection or sepsis. 3.1. Embryological development of the ureter Physiological dilatation during embryological development may result from the slow maturation and canalization of the excretory system [25,26]. This observation is the basis of the theory that strictures of the ureteropelvic and ureterovesical junctions may arise from incomplete recanalization of the ureter. 3.2. Fetal crossing vessels Allen [27] showed that the main areas where congenital strictures commonly develop correspond to the sites of temporary fetal crossing vessels. By contrast, older children undergoing pyeloplasty because of symptomatic pelvi-ureteric junction obstruction most often (30–50%) have extrinsic pressure from persisting crossing renal vessels [28]. 3.3. The impact of fetal vesico-ureteral reflux The effect of VUR on the fetal kidney can express itself in a global manner as urinary tract dilatation, focal renal damage and scarring. The consequence may be more pronounced in males, whose higher voiding pressures may accentuate the effects of VUR [29]. 3.4. The degree of maternal hydration The role of maternal hydration status as a cause of fetal pyelectasis is controversial. Some reports suggest that fetal renal pelvis anteroposterior diameter and amniotic fluid index increase with maternal hydration [30]. These findings may support physiologic theories that the influence of maternal hydration on renal pelvis dilatation is partially mediated via fetal urine production [31]. In contrast, other authors found no significant
Threshold value of renal pelvis (mm)
Gestation (weeks)
Incidence (%)
4 5 5 10 4 4 4 7
<20 20–24 <28 >28 – 18–23 <33 >33
2.2 4.4 5.5 3.9 4.5
change in the degree of fetal renal pyelectasis before and after maternal hydration [2,32]. 3.5. Other hypothesis Other hypothesis that have been suggested include the higher fetal urine flow during the third trimester [33], the influence of an endocrinologic or metabolic factor upon urinary tract tonicity in familial transmitted cases [34] and emptying of the fetal bladder that may be associated with a significant decrease in the size of the fetal renal pelvis [35].
4. Fetal renal pelvis dilatation and postnatal findings The tendency of renal pelvis dilatation to resolve spontaneously is supported by normal postnatal renal appearances reported in 36–80% of cases followed up after birth [15,36,37]. However, prenatally detected renal pelvis dilatation may be an indicator of significant urinary tract pathologies [38]. The likelihood of having a clinically significant uropathy is directly proportional to the severity of hydronephrosis [37]. A summary of the literature describing the postnatal uro-nephropathies found in neonates who presented with fetal renal pelvis dilatation is given in Table 2. The incidence and type of pathology varies considerably between studies, reflecting the differences in prenatal criteria and the variability in postnatal assessment. The 2 main pathologies found are pelvi-ureteric junction stenosis and VUR. 4.1. Renal pelvis dilatation and pelvi-ureteric junction stenosis Pelvi-ureteric junction stenosis occurs in 13% of children with antenatally diagnosed renal pelvis dilatation [37] and is characterized by obstruction at the level of the junction between the renal pelvis and the ureter. The anatomical basis for obstruction includes intrinsic stenosis/valves, peripelvic fibrosis, or crossing vessels
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Table 2 Incidence of uro-nephropathies in neonates with antenatally diagnosed renal pelvis dilatation Authors
Year
Threshold value of renal pelvis (mm)
Total
Abnormal (%)
PUJO (%)
VUR (%)
Megaureter (%)
Mild dilatation (%)
Duplex kidney (%)
Other (%)
Undergoing surgery (%)
Dudley et al. [36] Stocks et al. [39] Jaswon et al. [40] Ismaili et al. [37]
1997 1996 1999 2004
5 4–7 5 4–7
100 27 104 213
64 70 45 39
3 22 4 13
12 22 22 11
3
43 26 8 18*
4
7
5
4 3
3 11 1 3
7
PUJO (pelvi-ureteric junction obstruction), VUR (vesicoureteral reflux). * In this study mild and transient dilatations were considered as non significant findings.
[25]. In spite of the need to provide parents with a reliable prognosis concerning the future of infants with prenatally diagnosed pelvi-ureteric junction stenosis, postnatal management of these children has remained a controversial topic for the last 25 years [41]. This is due to specific difficulties related to these young children like the initial immaturity of the renal morphology and function and the progressive changes that will occur during growth. Expectancy and close follow-up [42] have progressively gained wide acceptance, although the surgical attitude, either systematic within the first months of life, or on the basis of variable morphological or functional parameters, is still the present attitude for many clinicians [43]. However, the final outcome, i.e. when these children have reached old age, is remote. What is apparent from different reports is that many attitudes are based on expert recommendations rather than objective data [44]. 4.2. Renal pelvis dilatation and vesico-ureteral reflux Renal pelvis dilatation can signal the presence of VUR in 11% [37] to 30% [45] of cases. VUR is currently central to the problems raised by the discovery of fetal renal pelvis dilatation. Some authors have therefore made a case for performing voiding cystourethrography (VCUG) in all infants presenting with antenatally detected renal pelvis dilatation irrespective of the degree of renal collecting system dilatation on postnatal US [39,40]. Nevertheless, a morerecent prospective study demonstrated that normal appearing urinary tract on 2 successive neonatal US rarely coexists with abnormal findings at VCUG. Therefore, in such patients, VCUG is not justified [46]. This opinion seems to be shared by more and more authors [47,48]. Furthermore, the necessity of diagnosing all cases of VUR has been questioned [49]. In contradiction with a widely held belief [50,51], VUR in infants with antenatally diagnosed renal pelvis dilatation was found in a large and prospective study to be of low-grade in 81% of cases with a high rate of 1year spontaneous resolution (70%) [46]. Therefore, it is
unclear whether reflux detected antenatally is clinically significant. It is even unclear whether asymptomatic antenatally detected VUR and symptomatic postnatal VUR are the same pathologies. In addition, in cases of reflux nephropathy, scarring may be congenital and therefore not preventable by early detection of VUR in this patient population [52].
5. Postnatal investigation of renal pelvis dilatation 5.1. Ultrasound The guiding principle in imaging must be to undertake appropriate investigations using the lowest radiation and least invasive techniques [8]. For that purpose, US is the first examination to perform after birth. It is usually the latter that determines the need for further investigations [36,46,48]. Neonatal US imaging is an attractive screening procedure because this technique provides many advantages: lack of ionizing radiation, wide feasibility and excellent anatomic resolution [53]. As compared to other imaging techniques, ultrasound imaging would minimize patient discomfort and avoid high cost as well as unjustified mobilization of health care resources. In babies with fetal renal pelvis dilatation, the presence of persistent urinary tract dilatation after birth seems to be the most important landmark; 7 mm is the most widely accepted upper limit of normal in the literature [54]. A recent study found that renal pelvis dilatation 7 mm represents 66% of abnormal postnatal US examinations. When present, this sonographic abnormality predicted underlying renal tract pathology in 73% of cases [37]. This study also showed that the presence of urinary upper tract dilatation is no longer the only sign of potential significant abnormality. When other ultrasonographic abnormalities [calyceal or ureteral dilatation, pelvic or ureteral wall thickening, absence of the corticomedullary differentiation and signs of renal dysplasia (small kidney, thinned or
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hyperechoic cortex and cortical cysts)] were found on postnatal US scan, significant nephro-uropathies were found in 70% of cases. Therefore, these ultrasonographic anomalies should be systematically looked for. In contrast, normal appearing urinary tract on neonatal ultrasound examinations was related to significant nephro-uropathies in only 3% of cases (low-grade primary VUR). Therefore, in such patients, further investigation is not justified. 5.2. Voiding cystourethrography The role of VCUG in the assessment of neonates with fetal renal pelvis dilatation must be permanently defined. Contradicting a recent editorial comment [55], a large prospective study [46] obtained an excellent sensitivity and negative predictive value when combining 2 screening meticulous neonatal US examinations and considering abnormalities in either of them as predictive of anomalies on VCUG. This study added weight to the growing body of evidence that postnatal follow up using VCUG solely on the basis of antenatally detected renal pelvis dilatation cannot be justified on the grounds that it will detect asymptomatic VUR mostly of a grade that is not clinically significant [47,48]. Furthermore, increasing parental awareness of symptoms of urinary tract infection by pediatric nephrologists and urologists could result in prompt self referral of ‘‘missed’’ cases [48]. 5.3. Intravenous pyelography and magnetic resonance imaging Imaging the urinary tract in babies with fetal renal pelvis dilatation has been mainly based on ultrasound and VCUG. Other complementary methods as intravenous pyelography and magnetic resonance imaging (MRI) may take part in the assessment of complicated cases. Intravenous urography has a limited role today in evaluating neonates and infants. Compared to intravenous pyelography, MRI has gained progressive acceptance for the evaluation of the urinary tract in children and the spectrum of applications increases steadily [56]. Limitations of MRI are mainly related to the need of sedation in infants and to the accessibility of the equipment. These limitations may explain why in a recent survey only 24% of pediatric nephrologists and 13% of pediatric urologists use MRI for the evaluation of infants with antenatally diagnosed high-grade hydronephrosis [57]. 5.4. Nuclear medicine Renography is an established technique with well defined capabilities and limitations. Radiotracers with high extraction rate such as Tc-99 m mercapto-acetyl-
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triglycine (MAG3) are preferred to glomerular tracers with low extraction rate such as Tc-99 m diethylene triamine pentaacetic acid (DTPA) [8,57]. Differential function is a robust and reproducible parameter if performed according to strict guidelines [58]. Determination of renal transit can be obtained by using simple parameters such as the time of maximum of the renogram (Tmax). Normal, slightly delayed or very delayed transit can be easily determined using this parameter [59]. In cases of marked renal stasis on the basic renogram, it may be complemented by a provocative test, namely the response to intravenous injection of furosemide [60]. In simple stasis, the retained radioactivity in the urinary tract is washed out rapidly by increased urine flow, whereas renal emptying is slow or nonexistent in true urine flow impairment [61]. However, drainage from the renal pelvis is dependent on both volume of the pelvis and flow. Thus the lack of drainage does not necessarily imply obstruction but could simply be due to an imbalance between volume and flow [61,62].
6. The future Perinatal uro-nephrology is a blooming discipline and has an exciting and promising future. Thanks to the increasing number of recent prospective studies, the work-up of antenatal renal pelvis dilatation is now better standardized. Nevertheless, many areas of controversy still remain and there is a need to continuously reassess our approach to global medical care of these infants. 6.1. Multidisciplinary perinatal activity The majority of pediatric urologists and nephrologists regularly ensure postnatal follow-up of babies with antenatally diagnosed renal pelvis dilatation in their daily practice but only 65% of them participate regularly to multidisciplinary perinatal staff meetings [57]. Yet, it is mandatory to establish registries of antenatally diagnosed urinary tract abnormalities within a multidisciplinary framework including colleagues in obstetrics, radiology, neonatology, pathology and genetics because there is a great need for properly designed collaborative and prospective longterm studies to produce large series of patients submitted to the same protocol that will allow developing stringent evidence-based guidelines in the future. 6.2. Areas of future research 6.2.1. Prenatal magnetic resonance imaging It is clear that prenatal US scanning results in the detection of many renal abnormalities and has pro-
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foundly altered the spectrum of diseases seen by pediatric urologists and nephrologists [63]. Now, the degree of accuracy of US is limited in some complicated cases of fetal renal pelvis dilatation. Therefore, the place of prenatal MRI scanning for determination of the anatomy of complicated nephro-uropathies takes a growing place in perinatal medicine. A recent study showed that prenatal MRI was useful as complementary technique in the assessment of unusual cases with inconclusive sonographic findings [64]. However, the definitive role of prenatal MRI still needs to be defined in future studies. 6.2.2. Antibiotic prophylaxis At our best knowledge, no current controlled studies support a role for continuous urinary antibiotic prophylaxis in the prevention of renal scars as compared to treatment of each episode of pyelonephritis as it occurs in VUR found in neonates who presented with fetal renal pelvis dilatation [65]. As others [49], we advocate the need of prospective randomized placebo-controlled trials to prove the benefit of prophylactic antimicrobial therapy. Smellie and colleagues [66] declare that this would be unethical in a neonatal population, and this opinion is shared by other authors in recent reports [67]. Our opinion is that the lack of support for a therapeutic modality which has been used for more than 3 decades is unacceptable. 6.2.3. Management of pelvi-ureteric junction stenosis Endless debate is offered in the literature concerning the surgical and conservative attitude and the long term effect on renal function as obtained from nuclear medicine tests in pelvi-ureteric junction stenosis. Unfortunately, the pros [68] and cons [69] on performing early pyeloplasty have failed to produce robust randomized studies. The follow up of either expectant or early surgical treatment is not long enough to reveal if the good results during the first 5–10 years are to stay for the rest of these patient’s lives. Large university centers investigating these children have the obligation to evaluate on the long course, in both the operated and non-operated patients, potential complications such as loss of renal function, urosepsis, stones or secondary tubular disease. Therefore, attempts to refine and sharpen our diagnostic accuracy of obstructive uropathy are urgent. For this purpose some innovations have held out much hope and would be of immense help in the future: MR imaging [56], color flow Doppler [70] and urine biochemistry [monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor- b1 (TGF- b1)] [71].
Fig. 2. Algorithm of a rational postnatal imaging strategy in infants with fetal renal pelvis dilatation.
7. Conclusions The third-trimester threshold value for the anteroposterior renal pelvis diameter of 7 mm is beyond any doubt the best prenatal criterion both for the screening of urinary tract dilatation and for the selection of patients needing postnatal investigation. Yet, in cases where only a second-trimester fetal examination is performed, a 4-mm threshold value for antero-posterior pelvis diameter should be used as a warning sign because this finding may reveal a significant urologic abnormality in 12% of cases. Based on our own experience [9,37,46,54], we propose in Fig. 2 our algorithm for a rational postnatal imaging strategy. Prenatal diagnosis of renal pelvis dilatation should initiate routine postnatal investigation including 2 renal US scans performed around day 5 and 1 month. When these neonatal US examinations are normal, no more investigations are required. Because many antenatally detected uropathies have shown the potential to resolve spontaneously, surgery is performed only after a period of observation. Now, since no definitive criteria are published, the circumstances in which surgical treatment is advocated by the different experts still remain a matter of institutional preference rather than evidence based medicine.
Acknowledgements Supported by a grant from The Belgian Kids Foundation (to Dr K. Ismaili).
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[46] Ismaili K, Avni FE, Hall M. Results of systematic voiding cystourethrography in infants with antenatally diagnosed renal pelvis dilation. J Pediatr 2002;141:21–4. [47] Acton C, Pahuja M, Opie G. Woodward A. A 5-year audit of 778 neonatal renal scans (Part 1): perplexing pyelectasis and suggested protocol for investigation. Australas Radiol 2003;47:349–53. [48] Moorthy I, Joshi N, Cook JV, Warren M. Antenatal hydronephrosis: negative predictive value of normal postnatal ultrasound, a 5-year study. Clin Radiol 2003;58:964–70. [49] Garin EH, Campos A, Homsy Y. Primary vesicoureteral reflux: review of current concepts. Pediatr Nephrol 1998;12:249–56. [50] Elder JS. Commentary: importance of antenatal diagnosis of vesicoureteral reflux. J Urol 1992;148:1750–4. [51] Yeung CK, Godley ML, Dhillon HK, Gordon I, Duffy PG, Ransley PG. The characteristics of primary vesico-ureteric reflux in male and female infants with prenatal hydronephrosis. Br J Urol 1997;80:319– 27. [52] Hiraoka M, Hori C, Tsukahara H, Kasuga K, Ishihara Y, Sudo M. Congenitally small kidneys with reflux as a common cause of nephropathy in boys. Kidney Int 1997;52:811–6. [53] Dacher JN. Diagnostic procedures excluding MRI, nuclear medicine, and video-urodynamics. In: Fotter R, editor. Pediatric uroradiology. Berlin Heidelberg New York: Springer; 2001. p. 1–14. [54] Avni EF, Ayadi K, Rypens F, Hall M, Schulman CC. Can careful ultrasound examination of the urinary tract exclude vesicoureteric reflux in the neonate? Br J Radiol 1997;70:977–82. [55] Wan J. Editorial comment. Urology 2004;61:1242–3. [56] Avni EF, Bali MA, Regnault M, Damry N, Degroot F, Metens T, et al. MR urography in children. Eur J Radiol 2002;43:154–66. [57] Ismaili K, Avni FE, Wissing KM, Piepsz A, Aubert D, Cochat P, et al. Current management of infants with fetal renal pelvis dilatation: a survey by French-speaking pediatric nephrologists and urologists. Pediatr Nephrol 2004;19:966–71. [58] Gordon I, Colarinha P, Fettich J, Fischer S, Fro¨ kier J, Hahn K, et al. Paediatric Committee of the European Association of Nuclear Medicine. Guidelines for standard and diuretic renography in children. Eur J Nuc Med 2001;28:BP21–30.
[59] Piepsz A, Tondeur M, Ham H. 99mTc-MAG 3 renal uptake: reproducibility and accuracy. J Nucl Med 1999;40:972–6. [60] Avni FE, Hall M. Diagnostic imaging. In: Avner ED, Harmon WE, Niaudet P, editors. Pediatric Nephrology. 5th ed. Philadelphia: Lippincot Williams and Wilkins; 2004. p. 449–73. [61] Piepsz A. Radionuclide studies in paediatric nephro-urology. Eur J Radiol 2002;43:146–53. [62] Gordon I. Diuretic renography in infants with prenatal unilateral hydronephrosis: an explanation for the controversy about poor drainage. BJU Int 2001;87:551–5. [63] Thomas DFM. Prenatal diagnosis: does it alter outcome? Prenat Diagn 2001;21:1004–11. [64] Cassart M, Massez A, Metens T, Rypens F, Lambot MA, Hall M, et al. Complementary role of MRI after sonography in assessing bilateral urinary tract anomalies in the fetus. AJR Am J Roentgenol 2004;182:689–95. [65] Williams G, Lee A, Craig J. Antibiotics for the prevention of urinary tract infection in children: A systematic review of randomized controlled trials. J Pediatr 2001;6:868–74. [66] Smellie JM, Prescod NP, Shaw PJ, Risdon RA, Bryant TN. Childhood reflux and urinary infection: a follow-up of 10-41 years in 226 adults. Pediatr Nephrol 1998;12:727–36. [67] Ylinen E, Ala-Houlala M, Wikstro¨ m S. Risk of renal scarring in vesicoureteral reflux detected either antenatally or during the neonatal period. Urology 2004;61:1238–42. [68] Hanna MK. Antenatal hydronephrosis and ureteropelvic junction obstruction: the case for early intervention. Urology 2000;55: 612–5. [69] Onen A, Jayanthi R, Koff SA. Long-term follow-up of prenatally detected severe bilateral newborn hydronephrosis initially managed nonoperatively. J Urol 2002;168:1118–20. [70] Patti G, Menghini ML, Todini AR, Marrocco G, Calisti A. The role of the renal resistive index ratio in diagnosing obstruction and in the follow-up of children with unilateral hydronephrosis. BJU Int 2000;85:308–12. [71] Chevalier RL. Biomarkers of congenital obstructive nephropathy: past, present and future. J Urol 2004;172:852–7.
European Urology 48 (2005) 207–214
ReviewPaediatric and Reconstructive Urology
Insights into the Pathogenesis and Natural History of Fetuses with Renal Pelvis Dilatation Khalid ismailia,*, Michelle Halla, Amy Piepszb, Marc Alexanderc, Claude Schulmand, Fred E. Avnie a
Department of Perinatal and Pediatric Nephrology, Hoˆpital Universitaire des Enfants – Reine Fabiola, 15, Avenue J.J. CROCQ, 1020–Brussels, Belgium b Department of Nuclear Medicine. Centre Hospitalier Universitaire St. Pierre c Department of Pediatrics. Centre Hospitalier Etterbeek-Ixelles d Department of Urology, Hoˆpital Erasme e Department of Radiology, Hoˆpital Erasme, Universite´ Libre de Bruxelles (ULB), Brussels, Belgium Accepted 15 February 2005 Available online 16 March 2005
Abstract Fetal renal pelvis dilatation is a frequent abnormality that has been observed in 4.5% of pregnancies. The majority of these cases have a tendency to resolve during infancy. Nevertheless, fetal renal pelvis dilatation may be due to significant structural abnormalities such as pelvi-ureteric junction stenosis or vesico-ureteral reflux that may adversely affect renal function or cause urinary infection or sepsis. This review article aims to summarize the data regarding fetal renal pelvis dilatation and to analyze controversial attitudes in the light of the various lines of practice, and to present rational antenatal and postnatal investigation strategy. # 2005 Elsevier B.V. All rights reserved. Keywords: Vesico-ureteral reflux; Fetal hydronephrosis; Urinary tract pathology; Ultrasonography
1. Introduction The introduction of routine fetal ultrasonographic examination has improved the detection rate of fetal anomalies, while the technical developments of ultrasound (US) equipment have increased diagnostic accuracy. This has led to the discovery of many fetal anomalies, and among them, upper urinary tract dilatation (Fig. 1) represents one of the largest groups amenable to neonatal management [1]. This finding, which may be recognized from the beginning of the second trimester of pregnancy, was assumed in early reports to be physiologic or nonobstructive, and therefore follow-up was not always obtained after the initial Abbreviations: MRI, Magnetic resonance imaging; US, Ultrasound; VCUG, Voiding cystourethrography; VUR, Vesico-ureteral reflux. * Corresponding author. Tel. +32 2 4772152; Fax: +32 2 4772154. E-mail address: [email protected] (K. ismaili).
identification [2,3]. Nevertheless, renal pelvic dilatation can be an early sonographic sign of fetal hydronephrosis [4], or as a marker of other abnormalities such as renal duplication or vesico-ureteral reflux (VUR) which cannot be easily identified by US during pregnancy [5]. Therefore, the patient is now presenting to the urologist or pediatric nephrologist before the baby is even born, with a presumptive diagnosis rather than a symptom. The detection of any fetal abnormality, including renal pelvis dilatation, generates considerable parental concern. Nevertheless, the expecting mother should be adequately informed of renal pelvis dilatation and its clinical significance [6]. Therefore, it is essential to have a clear idea of the range of potential differential diagnoses and likely outcome in order to make rational decisions concerning the treatment of these babies. There have been numerous articles discussing the significance of fetal renal pelvis dilatation as indicator
0302-2838/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.02.014
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Fig. 1. Prenatal ultrasound showing transverse view of a right renal pelvis dilatation. K (kidney), Sp (spine), DR (right), D (diameter).
of certain developmental abnormalities in the urinary tract. However, the long-term clinical implications of this condition have rarely been established in large and prospective cohort studies [7,8].
2. Definition and incidence Fetal renal pelvis dilatation is a frequent abnormality that has been observed in 4.5% of pregnancies [9]. Nevertheless, some controversy exists in the literature regarding the definition and significance of this finding. Pyelectasis is defined as dilatation of the renal pelvis whereas pyelocaliectasis and hydronephrosis include dilatation of calyces. Practically, the three terms are interchanged and all used as descriptions of a dilated renal collecting system, regardless of its etiology [1]. The majority of authors use the antero-posterior renal pelvis diameter system for classification of fetal renal pelvis dilatation. The Society for Fetal Urology (SFU) system [4] has another classification based upon calyceal dilatation rather than renal pelvic dilatation, but it is deemed to be less easily reproducible [10]. The first measurements of the antero-posterior fetal renal pelvis diameter in the 80’s suggested that a threshold value of 10 mm indicated the need for a full investigation of the urinary tract in early postnatal life [11]. The routine use of prenatal US with sufficiently sophisticated machines allowed the detection of smaller dilatations. In the early 90’s, the analysis of Corteville’s retrospective study [12] has demonstrated that the use of pyelectasis threshold values diameters of 4 mm in the second trimester and 7 mm in the third trimester of pregnancy permitted a more effective detection of urinary tract anomalies. Yet, more recent studies have
shown that the incidence of fetal pyelectasis is much higher when such small threshold diameters are used (Table 1). Very few studies have attempted to correct cut-off values for gestational age [5]. A notable exception is a recent prospective study that assessed the significance of renal pelvic diameters at different stages in gestation by correlating 16,929 measurements with the postnatal outcome [9]. This study concluded that 76% of dilatations, mostly between 4 and 7 mm, had been detected in the second trimester. In this series, only 12% of kidneys turned out to be linked to a significant nephrourological malformation, mostly VUR, when the antero-posterior dimension remained less than 7 mm in the third trimester. Simeoni et al. [17] have suggested that only pelvic dilatation greater than 10 mm after 28 weeks of gestation necessitates postnatal investigation. Other authors [9,18] did not confirm this statement. The proportion of abnormal kidneys diagnosed after birth seems significantly higher when using a third-trimester cut-off point of antero-posterior fetal renal pelvis diameter of 7 mm in comparison with a cut-off point of 10 mm. Besides the degree of fetal renal collecting system dilatation, other prognostic predictors of outcome include [1]: 1. 2. 3. 4.
The involvement of both kidneys. The presence of coexisting renal dysplasia. A decreased amount of amniotic fluid. Coexisting associated anomalies, which may eventually lead to karyotyping. 5. Significant modification of fetal urine biochemical markers that may have some role in predicting poor renal function postnatally. High sodium (>100 mEq/l after 20 weeks) [19], high calcium (>1.2 mmol/l) [20] and high b2-microglobulin (>2 mg/l) [19]. Nevertheless, the accuracy of these parameters is far from perfect [21]. 6. Fetal blood sampling probably poses greater risks than urine sampling, but allows measurement of better index of fetal glomerular filtration rate [21]. Serum b2-microglobulin could be of clinical interest only when extreme values are found (<3.5 mg/l good outcome; > 5 mg/l poor outcome) [22].
3. Pathophysiology There are several theories that account for the visibility of the renal pelvis during pregnancy. The distension of the urinary collecting system may be a
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Table 1 Definition and reported incidence of isolated renal pelvis dilatation Authors
Number of fetuses screened
Morin et al. [13]
5900
Langer et al. [14]
2170
Persutte et al. [15] Thompson and Thilaganathan [16] Ismaili et al. [9]
5529 10971 5643
dynamic and physiologic process [23]. Recently, Persutte et al. found the size of the fetal renal collecting system to be highly variable over the course of a 2-hour period [24]. Nevertheless, pyelectasis may be due to significant structural abnormalities that may adversely affect renal function or cause urinary infection or sepsis. 3.1. Embryological development of the ureter Physiological dilatation during embryological development may result from the slow maturation and canalization of the excretory system [25,26]. This observation is the basis of the theory that strictures of the ureteropelvic and ureterovesical junctions may arise from incomplete recanalization of the ureter. 3.2. Fetal crossing vessels Allen [27] showed that the main areas where congenital strictures commonly develop correspond to the sites of temporary fetal crossing vessels. By contrast, older children undergoing pyeloplasty because of symptomatic pelvi-ureteric junction obstruction most often (30–50%) have extrinsic pressure from persisting crossing renal vessels [28]. 3.3. The impact of fetal vesico-ureteral reflux The effect of VUR on the fetal kidney can express itself in a global manner as urinary tract dilatation, focal renal damage and scarring. The consequence may be more pronounced in males, whose higher voiding pressures may accentuate the effects of VUR [29]. 3.4. The degree of maternal hydration The role of maternal hydration status as a cause of fetal pyelectasis is controversial. Some reports suggest that fetal renal pelvis anteroposterior diameter and amniotic fluid index increase with maternal hydration [30]. These findings may support physiologic theories that the influence of maternal hydration on renal pelvis dilatation is partially mediated via fetal urine production [31]. In contrast, other authors found no significant
Threshold value of renal pelvis (mm)
Gestation (weeks)
Incidence (%)
4 5 5 10 4 4 4 7
<20 20–24 <28 >28 – 18–23 <33 >33
2.2 4.4 5.5 3.9 4.5
change in the degree of fetal renal pyelectasis before and after maternal hydration [2,32]. 3.5. Other hypothesis Other hypothesis that have been suggested include the higher fetal urine flow during the third trimester [33], the influence of an endocrinologic or metabolic factor upon urinary tract tonicity in familial transmitted cases [34] and emptying of the fetal bladder that may be associated with a significant decrease in the size of the fetal renal pelvis [35].
4. Fetal renal pelvis dilatation and postnatal findings The tendency of renal pelvis dilatation to resolve spontaneously is supported by normal postnatal renal appearances reported in 36–80% of cases followed up after birth [15,36,37]. However, prenatally detected renal pelvis dilatation may be an indicator of significant urinary tract pathologies [38]. The likelihood of having a clinically significant uropathy is directly proportional to the severity of hydronephrosis [37]. A summary of the literature describing the postnatal uro-nephropathies found in neonates who presented with fetal renal pelvis dilatation is given in Table 2. The incidence and type of pathology varies considerably between studies, reflecting the differences in prenatal criteria and the variability in postnatal assessment. The 2 main pathologies found are pelvi-ureteric junction stenosis and VUR. 4.1. Renal pelvis dilatation and pelvi-ureteric junction stenosis Pelvi-ureteric junction stenosis occurs in 13% of children with antenatally diagnosed renal pelvis dilatation [37] and is characterized by obstruction at the level of the junction between the renal pelvis and the ureter. The anatomical basis for obstruction includes intrinsic stenosis/valves, peripelvic fibrosis, or crossing vessels
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Table 2 Incidence of uro-nephropathies in neonates with antenatally diagnosed renal pelvis dilatation Authors
Year
Threshold value of renal pelvis (mm)
Total
Abnormal (%)
PUJO (%)
VUR (%)
Megaureter (%)
Mild dilatation (%)
Duplex kidney (%)
Other (%)
Undergoing surgery (%)
Dudley et al. [36] Stocks et al. [39] Jaswon et al. [40] Ismaili et al. [37]
1997 1996 1999 2004
5 4–7 5 4–7
100 27 104 213
64 70 45 39
3 22 4 13
12 22 22 11
3
43 26 8 18*
4
7
5
4 3
3 11 1 3
7
PUJO (pelvi-ureteric junction obstruction), VUR (vesicoureteral reflux). * In this study mild and transient dilatations were considered as non significant findings.
[25]. In spite of the need to provide parents with a reliable prognosis concerning the future of infants with prenatally diagnosed pelvi-ureteric junction stenosis, postnatal management of these children has remained a controversial topic for the last 25 years [41]. This is due to specific difficulties related to these young children like the initial immaturity of the renal morphology and function and the progressive changes that will occur during growth. Expectancy and close follow-up [42] have progressively gained wide acceptance, although the surgical attitude, either systematic within the first months of life, or on the basis of variable morphological or functional parameters, is still the present attitude for many clinicians [43]. However, the final outcome, i.e. when these children have reached old age, is remote. What is apparent from different reports is that many attitudes are based on expert recommendations rather than objective data [44]. 4.2. Renal pelvis dilatation and vesico-ureteral reflux Renal pelvis dilatation can signal the presence of VUR in 11% [37] to 30% [45] of cases. VUR is currently central to the problems raised by the discovery of fetal renal pelvis dilatation. Some authors have therefore made a case for performing voiding cystourethrography (VCUG) in all infants presenting with antenatally detected renal pelvis dilatation irrespective of the degree of renal collecting system dilatation on postnatal US [39,40]. Nevertheless, a morerecent prospective study demonstrated that normal appearing urinary tract on 2 successive neonatal US rarely coexists with abnormal findings at VCUG. Therefore, in such patients, VCUG is not justified [46]. This opinion seems to be shared by more and more authors [47,48]. Furthermore, the necessity of diagnosing all cases of VUR has been questioned [49]. In contradiction with a widely held belief [50,51], VUR in infants with antenatally diagnosed renal pelvis dilatation was found in a large and prospective study to be of low-grade in 81% of cases with a high rate of 1year spontaneous resolution (70%) [46]. Therefore, it is
unclear whether reflux detected antenatally is clinically significant. It is even unclear whether asymptomatic antenatally detected VUR and symptomatic postnatal VUR are the same pathologies. In addition, in cases of reflux nephropathy, scarring may be congenital and therefore not preventable by early detection of VUR in this patient population [52].
5. Postnatal investigation of renal pelvis dilatation 5.1. Ultrasound The guiding principle in imaging must be to undertake appropriate investigations using the lowest radiation and least invasive techniques [8]. For that purpose, US is the first examination to perform after birth. It is usually the latter that determines the need for further investigations [36,46,48]. Neonatal US imaging is an attractive screening procedure because this technique provides many advantages: lack of ionizing radiation, wide feasibility and excellent anatomic resolution [53]. As compared to other imaging techniques, ultrasound imaging would minimize patient discomfort and avoid high cost as well as unjustified mobilization of health care resources. In babies with fetal renal pelvis dilatation, the presence of persistent urinary tract dilatation after birth seems to be the most important landmark; 7 mm is the most widely accepted upper limit of normal in the literature [54]. A recent study found that renal pelvis dilatation 7 mm represents 66% of abnormal postnatal US examinations. When present, this sonographic abnormality predicted underlying renal tract pathology in 73% of cases [37]. This study also showed that the presence of urinary upper tract dilatation is no longer the only sign of potential significant abnormality. When other ultrasonographic abnormalities [calyceal or ureteral dilatation, pelvic or ureteral wall thickening, absence of the corticomedullary differentiation and signs of renal dysplasia (small kidney, thinned or
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hyperechoic cortex and cortical cysts)] were found on postnatal US scan, significant nephro-uropathies were found in 70% of cases. Therefore, these ultrasonographic anomalies should be systematically looked for. In contrast, normal appearing urinary tract on neonatal ultrasound examinations was related to significant nephro-uropathies in only 3% of cases (low-grade primary VUR). Therefore, in such patients, further investigation is not justified. 5.2. Voiding cystourethrography The role of VCUG in the assessment of neonates with fetal renal pelvis dilatation must be permanently defined. Contradicting a recent editorial comment [55], a large prospective study [46] obtained an excellent sensitivity and negative predictive value when combining 2 screening meticulous neonatal US examinations and considering abnormalities in either of them as predictive of anomalies on VCUG. This study added weight to the growing body of evidence that postnatal follow up using VCUG solely on the basis of antenatally detected renal pelvis dilatation cannot be justified on the grounds that it will detect asymptomatic VUR mostly of a grade that is not clinically significant [47,48]. Furthermore, increasing parental awareness of symptoms of urinary tract infection by pediatric nephrologists and urologists could result in prompt self referral of ‘‘missed’’ cases [48]. 5.3. Intravenous pyelography and magnetic resonance imaging Imaging the urinary tract in babies with fetal renal pelvis dilatation has been mainly based on ultrasound and VCUG. Other complementary methods as intravenous pyelography and magnetic resonance imaging (MRI) may take part in the assessment of complicated cases. Intravenous urography has a limited role today in evaluating neonates and infants. Compared to intravenous pyelography, MRI has gained progressive acceptance for the evaluation of the urinary tract in children and the spectrum of applications increases steadily [56]. Limitations of MRI are mainly related to the need of sedation in infants and to the accessibility of the equipment. These limitations may explain why in a recent survey only 24% of pediatric nephrologists and 13% of pediatric urologists use MRI for the evaluation of infants with antenatally diagnosed high-grade hydronephrosis [57]. 5.4. Nuclear medicine Renography is an established technique with well defined capabilities and limitations. Radiotracers with high extraction rate such as Tc-99 m mercapto-acetyl-
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triglycine (MAG3) are preferred to glomerular tracers with low extraction rate such as Tc-99 m diethylene triamine pentaacetic acid (DTPA) [8,57]. Differential function is a robust and reproducible parameter if performed according to strict guidelines [58]. Determination of renal transit can be obtained by using simple parameters such as the time of maximum of the renogram (Tmax). Normal, slightly delayed or very delayed transit can be easily determined using this parameter [59]. In cases of marked renal stasis on the basic renogram, it may be complemented by a provocative test, namely the response to intravenous injection of furosemide [60]. In simple stasis, the retained radioactivity in the urinary tract is washed out rapidly by increased urine flow, whereas renal emptying is slow or nonexistent in true urine flow impairment [61]. However, drainage from the renal pelvis is dependent on both volume of the pelvis and flow. Thus the lack of drainage does not necessarily imply obstruction but could simply be due to an imbalance between volume and flow [61,62].
6. The future Perinatal uro-nephrology is a blooming discipline and has an exciting and promising future. Thanks to the increasing number of recent prospective studies, the work-up of antenatal renal pelvis dilatation is now better standardized. Nevertheless, many areas of controversy still remain and there is a need to continuously reassess our approach to global medical care of these infants. 6.1. Multidisciplinary perinatal activity The majority of pediatric urologists and nephrologists regularly ensure postnatal follow-up of babies with antenatally diagnosed renal pelvis dilatation in their daily practice but only 65% of them participate regularly to multidisciplinary perinatal staff meetings [57]. Yet, it is mandatory to establish registries of antenatally diagnosed urinary tract abnormalities within a multidisciplinary framework including colleagues in obstetrics, radiology, neonatology, pathology and genetics because there is a great need for properly designed collaborative and prospective longterm studies to produce large series of patients submitted to the same protocol that will allow developing stringent evidence-based guidelines in the future. 6.2. Areas of future research 6.2.1. Prenatal magnetic resonance imaging It is clear that prenatal US scanning results in the detection of many renal abnormalities and has pro-
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foundly altered the spectrum of diseases seen by pediatric urologists and nephrologists [63]. Now, the degree of accuracy of US is limited in some complicated cases of fetal renal pelvis dilatation. Therefore, the place of prenatal MRI scanning for determination of the anatomy of complicated nephro-uropathies takes a growing place in perinatal medicine. A recent study showed that prenatal MRI was useful as complementary technique in the assessment of unusual cases with inconclusive sonographic findings [64]. However, the definitive role of prenatal MRI still needs to be defined in future studies. 6.2.2. Antibiotic prophylaxis At our best knowledge, no current controlled studies support a role for continuous urinary antibiotic prophylaxis in the prevention of renal scars as compared to treatment of each episode of pyelonephritis as it occurs in VUR found in neonates who presented with fetal renal pelvis dilatation [65]. As others [49], we advocate the need of prospective randomized placebo-controlled trials to prove the benefit of prophylactic antimicrobial therapy. Smellie and colleagues [66] declare that this would be unethical in a neonatal population, and this opinion is shared by other authors in recent reports [67]. Our opinion is that the lack of support for a therapeutic modality which has been used for more than 3 decades is unacceptable. 6.2.3. Management of pelvi-ureteric junction stenosis Endless debate is offered in the literature concerning the surgical and conservative attitude and the long term effect on renal function as obtained from nuclear medicine tests in pelvi-ureteric junction stenosis. Unfortunately, the pros [68] and cons [69] on performing early pyeloplasty have failed to produce robust randomized studies. The follow up of either expectant or early surgical treatment is not long enough to reveal if the good results during the first 5–10 years are to stay for the rest of these patient’s lives. Large university centers investigating these children have the obligation to evaluate on the long course, in both the operated and non-operated patients, potential complications such as loss of renal function, urosepsis, stones or secondary tubular disease. Therefore, attempts to refine and sharpen our diagnostic accuracy of obstructive uropathy are urgent. For this purpose some innovations have held out much hope and would be of immense help in the future: MR imaging [56], color flow Doppler [70] and urine biochemistry [monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor- b1 (TGF- b1)] [71].
Fig. 2. Algorithm of a rational postnatal imaging strategy in infants with fetal renal pelvis dilatation.
7. Conclusions The third-trimester threshold value for the anteroposterior renal pelvis diameter of 7 mm is beyond any doubt the best prenatal criterion both for the screening of urinary tract dilatation and for the selection of patients needing postnatal investigation. Yet, in cases where only a second-trimester fetal examination is performed, a 4-mm threshold value for antero-posterior pelvis diameter should be used as a warning sign because this finding may reveal a significant urologic abnormality in 12% of cases. Based on our own experience [9,37,46,54], we propose in Fig. 2 our algorithm for a rational postnatal imaging strategy. Prenatal diagnosis of renal pelvis dilatation should initiate routine postnatal investigation including 2 renal US scans performed around day 5 and 1 month. When these neonatal US examinations are normal, no more investigations are required. Because many antenatally detected uropathies have shown the potential to resolve spontaneously, surgery is performed only after a period of observation. Now, since no definitive criteria are published, the circumstances in which surgical treatment is advocated by the different experts still remain a matter of institutional preference rather than evidence based medicine.
Acknowledgements Supported by a grant from The Belgian Kids Foundation (to Dr K. Ismaili).
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