Curr Urol Rep (2014) 15:430 DOI 10.1007/s11934-014-0430-5

PEDIATRIC UROLOGY (M CASTELLAN AND R GOSALBEZ, SECTION EDITORS)

Prenatal Hydronephrosis: Postnatal Evaluation and Management Vijaya Vemulakonda & Jenny Yiee & Duncan T. Wilcox

# Springer Science+Business Media New York 2014

Abstract Congenital hydronephrosis is one of the most common anomalies identified on antenatal ultrasound. The underlying etiology of congenital hydronephrosis is multifold, ranging from transient hydronephrosis in utero to clinically significant congenital anomalies of the kidney and urinary tract. While traditional management of hydronephrosis was aimed at relieving symptoms, the advent of routine prenatal ultrasound has led to a shift in the goal of treatment to prevention of renal injury in the asymptomatic patient. However, despite this focus on renal preservation, the diagnostic criteria for identification of children “at risk” for renal damage that can be alleviated by surgical treatment remain a subject of debate. Both antenatal and postnatal imaging studies have been evaluated as indicators for potential reversible renal damage and have been used as potential indicators of the need for surgical intervention. The aim of this review is to discuss the current literature regarding the role of postnatal clinical and radiographic evaluation to identify children who may benefit from early surgical intervention.

Keywords Hydronephrosis . Prenatal . Ultrasonography . Infant . Urology

Introduction Congenital hydronephrosis is one of the most common anomalies identified on antenatal ultrasound, affecting approximately 1 % of all pregnancies annually [1]. The underlying etiology of congenital hydronephrosis is multifold, ranging from transient hydronephrosis in utero to clinically significant congenital anomalies of the kidney and urinary tract [2]. Before prenatal ultrasound became widely available in the 1980s, children with hydronephrosis often presented with associated symptoms, such as infection, pain, hematuria, or palpable mass [1], and the primary role of surgical intervention was alleviation of these symptoms. The routine use of prenatal ultrasound has led to earlier diagnosis of the asymptomatic patient with an associated shift in treatment to renal preservation rather than symptomatic relief. This shift in treatment goals has led to new dilemmas in the treatment of these patients: how should patients with prenatal hydronephrosis be evaluated and what criteria should be used to identify those children who may benefit from surgical intervention [3, 4•, 5•, 6, 7]? This article will provide an overview of the current literature regarding the postnatal evaluation and management of cases of prenatally detected hydronephrosis that are suspicious for ureteropelvic junction obstruction.

Prenatal Detection This article is part of theTopical Collection on Pediatric Urology V. Vemulakonda (*) : D. T. Wilcox Department of Pediatric Urology, Children’s Hospital Colorado, 13123 East 16th Avenue, Campus Box B-463, Aurora, CO 80045, USA e-mail: [email protected] J. Yiee Department of Urology, Kaiser Permanente Southern California, Anaheim, CA, USA

Prenatal hydronephrosis is one of the most common findings on prenatal ultrasound, with an incidence of 1-5 % [8]. The most common clinically significant etiology of hydronephrosis is ureteropelvic junction obstruction, with an incidence of 1 in 1000, and accounting for 50 % of cases of high-grade hydronephrosis. Prenatal ultrasound has been used as an indicator of potential obstruction, with anterior-posterior diameter being the most widely used prenatal ultrasound measurement of obstruction risk. While higher measurements have been

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associated with an increased risk of postnatal pathology including ureteropelvic junction obstruction, there is no clear consensus regarding the ideal threshold for defining obstruction warranting surgical intervention. Furthermore, measurement is dependent on gestational age, bladder fullness, and maternal hydration status. As a result, prior studies have varied significantly in the level of dilation that warrants further evaluation and treatment [8]. Despite these limitations, clinically significant hydronephrosis has been proposed as being >10 mm in the second trimester and >15 mm in the third trimester [8], and prior studies have suggested that these cut-offs are associated with a >50 % likelihood of ureteropelvic junction obstruction on postnatal imaging [5•]. Similarly, other common etiologies of hydronephrosis are also more common in the setting of severe hydronephrosis, including posterior urethral valves (5.3 %) and ureterovesical junction obstruction (5.3 %) [5•]. Of note, vesicoureteral reflux is present in 5-15 % of cases of antenatal hydronephrosis and, unlike other urinary tract pathology, does not appear to be related to severity of hydronephrosis [8]. As a result, postnatal imaging may be warranted even in the setting of mild or resolved antenatal hydronephrosis. Due to the limitations of prenatal ultrasound, recent work has evaluated the potential role of fetal biomarkers in identifying infants at risk for renal injury. While beta (2)- macroglobulin has been utilized in cases of prenatally diagnosed posterior urethral valves, it has not been used in the setting of suspected unilateral obstruction due to its role as a surrogate for global renal function, rather than differential renal function [9]. Another potential marker of postnatal renal function is cystatin C; while this has been suggested as a potential predictor of impaired renal function in preliminary studies, this has not been validated in larger clinical trials [10]. As a result, while this area of research is promising, the optimal role of fetal serum and urinary biomarkers in the setting of suspected upper urinary tract obstruction has not yet been established.

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have transient hydronephrosis, the risk of associated pathology remains significant even in these cases. Contemporary series have suggested a risk of associated pathology in infants with mild antenatal hydronephrosis of upwards of 10 % [4•, 5•]. In these cases, almost 10 % of cases may have worsening of hydronephrosis on postnatal imaging, with over 5 % having evidence of pathology associated with renal impairment, such as high-grade vesicoureteral reflux and ureteropelvic junction obstruction [11]. In the setting of transient hydronephrosis, Ismaili et al. found that 12 % of infants with hydronephrosis in the second trimester with subsequent resolution in the third trimester were subsequently found to have clinically significant pathology on postnatal imaging [4•]. These findings suggest that at least a postnatal ultrasound screening may be of benefit even in cases of mild or transient antenatal hydronephrosis, although prospective large scale studies are needed to more clearly quantify the risk and the relative costs of widespread screening in this population. When Should Infants be Evaluated? Due to the impact of hydration status on ultrasound, initial postnatal ultrasound has traditionally been recommended after 48 hours of life. Some have recommended repeat ultrasound at 1–3 weeks in cases of mild or resolved hydronephrosis to minimize the potential risk of neonatal oliguria leading to underrepresentation of the degree of dilation [12]. A study by Wiener et al. suggested almost 50 % of patients may have increased hydronephrosis on ultrasound performed after one week of life [13]. However, despite this concern, the risk of surgical intervention in these patients does not seem to be impacted by the change in findings on repeat ultrasound, raising questions about the significance of early repeat ultrasound [13, 14]. However, due to the variability in ultrasound, a repeat ultrasound at 6–12 months of life is still recommended to rule out the risk of occult pathology [8]. What Additional Tests Should be Ordered?

Postnatal Evaluation Renal Ultrasound Who Should be Evaluated? The need for postnatal imaging and the extent of postnatal imaging is largely determined by the degree of antenatal hydronephrosis. The risk of postnatal pathology appears to be significant in cases of moderate to severe antenatal hydronephrosis, with incidence ranging from 45 % in moderate cases to over 80 % in severe cases [5•]. As a result, there is a general consensus that infants with moderate to severe antenatal hydronephrosis should undergo routine postnatal imaging. The role of postnatal imaging in infants with mild or resolved antenatal hydronephrosis is less clear. Although the majority of children with mild antenatal hydronephrosis will

Renal ultrasound remains the most widely used imaging modality in infants with antenatal hydronephrosis. This is largely due to wide availability, the low risk, and the absence of radiation exposure. However, the quality of ultrasound is dependent on patient hydration status and operator experience. As a result, ultrasound alone is relatively poor as a surgical predictor [15]. The most widely used classification system for postnatal hydronephrosis in the United States is the Society for Fetal Urology classification (Fig. 1), which was developed to aid in standardization of the evaluation and follow-up of hydronephrosis [8]. This system has previously been noted to have modest inter-rater but high intra-rater

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Fig. 1 Ultrasound appearance of hydronephrosis by Society for Fetal Urology (SFU) classification

reliability [16]. As discussed previously, in cases of mild or resolved hydronephrosis, where the risk of clinically significant urologic pathology is low, ultrasound is generally sufficient for postnatal monitoring [14]. However, in cases where lower tract pathology is suspected or in cases of high-grade hydronephrosis where obstruction is more likely, additional imaging is warranted.

Voiding Cystourethrography The traditional algorithm in evaluating hydronephrosis is to obtain a voiding cystourethrogram (VCUG) within the first few days of life [17]. This recommendation is based on the rationale that vesicoureteral reflux is a significant risk factor for renal infection and, consequently, renal injury. Furthermore, given that the risk of reflux and the grade of reflux do not appear to be associated with the degree of hydronephrosis [5•], VCUG is potentially beneficial in all infants with antenatal hydronephrosis. However, as the definition of clinically significant vesicoureteral reflux continues to evolve, so too does the role of screening VCUG. The invasiveness of the study and associated radiation exposure has heightened scrutiny regarding the optimal role of screening VCUG in the asymptomatic patient [18]. Furthermore, recent studies suggest that, in cases of mild hydronephrosis where lower tract pathology is not suspected, there is no clear benefit to early diagnosis or treatment of vesicoureteral reflux [19, 20]. Yerkes et al. found that, in patients with Society for Fetal Urology (SFU) grade 1–2 hydronephrosis, 15 % had evidence of reflux. However, in the subset of infants who did not undergo VCUG, none had evidence of subsequent pyelonephritis or renal injury, suggesting that VCUG may not be needed in these infants [20]. A similar prospective study of infants with antenatal hydronephrosis found that infants with moderate hydronephrosis (APD >7 mm) had a 40 % likelihood of an abnormal VCUG [21]. However, in infants with two normal postnatal ultrasounds, the risk of abnormal VCUG was <10 % [21]. As a result, the role of VCUG in the setting of mild or resolved hydronephrosis

continues to evolve, with significant variability in the use of screening VCUG in these patients [22].

Nuclear Renography Due to the limitations of ultrasound alone in predicting the risk of obstruction and need for surgical intervention, nuclear renography has been used as an adjunct in cases of highgrade (SFU 3–4) hydronephrosis where underlying obstruction is suspected [23]. The most common form of nuclear renography used in cases of suspected obstruction utilizes the Tc-mercaptoacetyltriglycine (MAG3) radiotracer. This tracer is primarily excreted by secretion from the proximal tubules rather than glomerular filtration [24]. As a result, it allows for measurement of both differential renal function as well as renal drainage. An initial renogram is generally obtained at least 6–8 weeks after birth to allow for renal maturation; however, the optimal timing of nuclear renography has not been clearly established. Although national urologic and radiologic organizations have developed guidelines to standardize use of this test, reliability remains an issue, with bilaterality of disease and practice variability leading to the possibility of false-negative tests [25]. Furthermore, concerns have been reported that renal function may be overrepresented in the large hydronephrotic kidney, further limiting potential interpretive results [8]. Despite these limitations, MAG3 renography may help to inform the decision for surgery. Prior studies have suggested that prolonged radiotracer clearance (T ½ >20 minutes) may be an indicator for obstruction amenable to surgical correction [26, 27]. However, the relative benefit of this metric in predicting the need for surgery remains controversial due to potential underestimation of drainage based on bladder fullness and gravity [28, 29]. A study by Koff et al. found that T ½ was not predictive of spontaneous improvement of hydronephrosis, with >50 % of infants with improvement of their hydronephrosis having obstructed T1/2 values [30]. As a result, some authors have recommended against using T1/2 at all in determining the potential need for surgery [31, 32•].

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As an alternative to T1/2, investigators have suggested utilizing impaired function (differential function<40 %) as indicative of the benefit of surgery [23, 32•]. Prior studies have suggested that postoperative function may be recovered in patients with mildly impaired preoperative function [33]. Similarly, Ulman et al. also reported the potential for recovery of function after pyeloplasty in infants with initial renal impairment [32•]. However, despite these reports of recovery of renal function, other authors have been less optimistic about the potential for recovery of renal function after pyeloplasty [34]. Furthermore, close observation is essential in cases where impaired renal function is utilized as the primary indicator for surgery [35]. As a result, many practitioners likely use a combination of factors, including changes in hydronephrosis on ultrasound, renal function, drainage patterns, and parental preferences, to determine when surgery would be beneficial [27, 36, 37]. Potential Role of Biomarkers A more recent area of study has been the use of serum and urinary biomarkers to predict the risk of obstruction and renal functional impairment in infants with antenatally detected hydronephrosis. These potential biomarkers have included: transforming growth factor beta 1 (TGF-β1), urinary monocyte chemotactic protein-1 (UCMP-1), urinary neutrophil gelatinase-associated lipocalin (NGAL), and beta-2- macroglobulin (β2-M). TGF- β1has been shown to be associated with renal dysplasia, acquired renal damage [38], and obstruction [39]. However, this marker has not been shown to be associated with halftime radiotracer clearance or hydronephrosis grade [40]. Furthermore, TGF-β1 is a nonspecific marker that may be elevated in other renal nephropathies [39]. UCMP-1 has also been evaluated as a potential marker of ureteropelvic junction obstruction. A recent case-control study showed that UCMP-1 is elevated in cases of obstruction and positively correlates with half-time radiotracer clearance and impaired differential renal function on MAG3. However, as with TGF- β1, UCMP-1 may be a nonspecific measure of renal injury rather than unique to obstructive nephropathy [41, 42]. Urinary NGAL and β2-M have both been studied as markers of preoperative obstruction and postoperative success. In their study of samples from 24 children, Madsen et al. found that NGAL and β2-M were both increased in patients with evidence of obstruction at the time of pyeloplasty and that these levels decreased to levels similar to healthy controls after surgical repair [43]. Similarly, Cost et al. found that NGAL levels were significantly higher in children with ureteropelvic obstruction and normalized after surgical correction. Of note, they also found that NGAL levels were inversely correlated with differential renal function of the affected kidney, suggesting that NGAL may serve as a

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marker both for obstruction and renal impairment in these patients [44]. These results suggest a potential role for urinary biomarkers to help stratify the risk of obstruction and of renal injury in infants with high-grade hydronephrosis. However, the optimal role of either a single biomarker or a panel of biomarkers in the clinical evaluation of these infants has yet to be clearly established.

Postnatal Management Unilateral Low-grade Hydronephrosis In cases of low-grade (SFU grade 1–2) unilateral hydronephrosis, the majority of cases are transient without significant risk of clinically significant pathology [45]. While this risk is relatively low, the incidence of associated pathology may be up to 30 % in some studies [45, 46]. Additionally, this risk appears to be increased in cases where there is worsening hydronephrosis on serial exams, which may occur in up to 5 % of cases [45, 47, 48]. As a result, the most recent SFU consensus statement suggests that repeat ultrasound at 3– 6 months may be beneficial in the evaluation of these patients with potential additional imaging such as nuclear renography in the setting of worsening hydronephrosis [8]. As discussed above, while vesicoureteral reflux may be present in up to 15 % of these patients [5•, 20], the true clinical significance of this finding in asymptomatic infants is unknown [20]. As a result, the role of VCUG in isolated unilateral low-grade hydronephrosis remains controversial and the authors do not routinely recommend screening VCUG in these patients in the absence of concern for associated lower tract pathology. Unilateral High-grade Hydronephrosis In cases of high-grade (SFU grade 3–4) hydronephrosis, the most common diagnosis is ureteropelvic junction obstruction, with an incidence of up to 50 % in SFU grade 3 [49], and over 80 % in cases of SFU grade 4 hydronephrosis where the AP diameter exceeds 40 mm [31]. Despite the high incidence of potential ureteropelvic junction (UPJ) obstruction in this setting, there has been a shift in management to close observation rather than early surgery in these patients. Studies by Koff et al. and Ransley et al. suggest that when renal function is the primary indicator for surgery the incidence of surgical intervention is less than 25 % in these patients [23, 50]. As a result, recent series have recommended close observation of these patients with surgical intervention only in cases where there is impaired function or loss of function, worsening hydronephrosis, or associated symptoms [27, 32•, 51, 52]. While an early MAG3 may be of benefit in establishing a

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baseline for following these children, ultrasound remains the primary imaging modality in these children and some authors recommend follow up MAG3 in the setting of worsening hydronephrosis or persistent high-grade hydronephrosis at one year of age [27]. Cases of late recurrence have been reported to occur over five years after initial diagnosis [49]. As a result, long-term follow-up may be beneficial, although the optimal duration and frequency of follow-up have not been adequately defined [8]. In cases of moderate to severe hydronephrosis, the risk of vesicoureteral reflux may be up to 15 % [5•]. Additionally, UPJ obstruction has also been associated with vesicoureteral reflux in approximately 15 % of cases [53]. As a result, VCUG has traditionally been recommended as part of the initial evaluation of these patients. However, given the current controversies and lack of clear data regarding the role of treatment in asymptomatic vesicoureteral reflux [54••], the potential benefit of VCUG in these patients requires further study. Bilateral Hydronephrosis The management of bilateral hydronephrosis is less wellestablished than for unilateral hydronephrosis. Due to the measurement of differential renal function, nuclear renography findings may be difficult to interpret. Additionally, the presence of bilateral upper tract dilation raises concerns regarding lower tract anomalies, such as posterior urethral valves, prune belly syndrome, and urethral atresia. As a result, early voiding cystourethrography is recommended to rule out lower tract obstruction that may require urgent intervention [55]. As in the case of unilateral hydronephrosis, serial ultrasounds and selective renography may be beneficial in assessing the risk of obstruction, with reports of surgical intervention due to renal impairment in upwards of 35 % of these patients [56]. However, due to the difficulty in interpretation of baseline functional assessment and concerns regarding bilateral renal impairment in these patients, close observation is recommended if early surgical intervention is not indicated. Is there a Role for Prophylactic Antibiotics? The role of prophylactic antibiotics in patients with antenatal hydronephrosis is controversial. While the rationale for prophylaxis is prevention of urinary tract infections (UTI) due to a potential increased risk in infants with hydronephrosis, the data to support this is not without its limitations. In a meta-analysis of 21 studies and 3,876 patients that assessed the role of antibiotic prophylaxis in infants with antenatal hydronephrosis, the authors indicated that the evidence was only moderate or low in

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quality [57]. Furthermore, recent studies have not shown a significant reduction in risk of UTI in infants with mild hydronephrosis on prophylaxis as compared to those who are not [58]. As a result, the role of antibiotic prophylaxis in mild hydronephrosis remains under investigation. In infants with high-grade hydronephrosis, the role for antibiotic prophylaxis has been more accepted despite the lack of clear evidence to support this. Lee et al. showed a significantly increased risk of UTI in infants with highgrade hydronephrosis [5•]. Similarly, data from a recent meta-analysis suggest that prophylactic antibiotics in this patient population reduced the risk of infection from 28.9 to 14.6 % [57]. However, a recent prospective cohort study of infants with suspected ureteropelvic junction obstruction showed no increased risk of UTI in these patients and no increased risk of pyelonephritis on DMSA in these patients, suggesting that the risk of febrile UTI in this population may not be as significant as previously considered. Furthermore, a retrospective study by Roth et al. showed no difference in the risk of UTI in infants with high-grade hydronephrosis who were on prophylaxis compared to those who were not [59]. These data suggest that the true risk of UTI in infants with hydronephrosis and the benefit of prophylaxis in these infants remain unclear.

Conclusions Antenatal hydronephrosis is one of the most common findings on antenatal ultrasound. While rare cases may be associated with pathology, such as posterior urethral valves that require urgent postnatal intervention, many cases of hydronephrosis can be safely observed. The optimal timing and types of imaging studies used to follow these patients and the optimal indications for surgery have not yet been definitively established. New markers of renal injury such as urinary biomarkers in the antenatal and postnatal setting offer promising potential for more accurate risk stratification of these patients in the near future. The optimal strategy for surveillance and surgical intervention continues to evolve as new data on the renal outcomes of these patients become available. Compliance with Ethics Guidelines Conflict of Interest Dr. Vijaya Vemulakonda, Dr. Jenny Yiee, and Dr. Duncan T. Wilcox declare that they have no conflicts of interest to report. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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