Obstructive Uropathies
INTRODUCTION
The urinary system is essential for the elimination of metabolic wastes, maintenance of physiologic pH, and the preservation of fluid and electrolyte homeostasis. It also contributes to vital functions like erythropoiesis and blood pressure control. Obstruction in the upper or lower urinary tract system can lead to disruption in these vital body physiologies and can lead to significant morbidity, which may be irreversible and ultimately lead to mortality. In neonates and young children, reports have shown that obstruction of the urinary tract is the most common cause of renal insufficiency, especially in boys under the age of 1, as well as the number 1 cause of renal transplantation in children.1,2 The majority of these obstructive uropathies are congenital in nature. The neonatal kidney is still developing, therefore obstruction can lead to alterations in the normal growth pattern and differentiation of the renal cells beginning in the intrauterine period and progressing postpartum, ultimately resulting in the development of fibrosis and renal failure. Obstruction can be limited to the upper urinary tract, the lower urinary tract, or a combination.
The main sign of obstructive uropathy is hydronephrosis, which involves dilation of the renal collecting system, including the renal pelvis and the renal calyces. Even the ureters may be dilated from the accumulation of urine in the collecting system. Genitourinary anomalies can be found in up to 0.2%–5% of pregnancies. Hydronephrosis comprises up to 87% of the identified anomalies. From prenatal ultrasound screening, varying degrees of hydronephrosis can be seen in up to 1.4% of fetuses, detected as early as the 12th week of pregnancy. More than half of these resolve spontaneously after birth. It is estimated that 48% are transient in nature (ie, from fetal folds in the proximal ureter during organogenesis), 15% are normal physiologic findings, 11% are from ureteropelvic junction (UPJ) obstruction, 9% are from vesicoureteral reflux (VUR), 4% are associated with congenital megaureters, and the others derive from miscellaneous causes (ie, from ureteroceles, posterior urethral valve [PUV], prune-belly syndrome [PBS]). There is a 2:1 male-to-female predominance of hydronephrosis. It can also be bilateral in 20%–40% of neonates.
Prenatal sonogram is mostly the means by which obstruction in the urinary tract is picked up in the developed world. If prenatal ultrasound was not obtained, neonatal presentations can range from palpable abdominal mass, urinary tract infections (UTIs), hematuria, failure to thrive, and occasionally renal failure. The risk of postnatal pathology from a prenatal finding of hydronephrosis has been correlated with the degree of the hydronephrosis seen. One meta-analysis reported 11.9% in cases of mild hydronephrosis and 45.1% in moderate and 88.3% in severe antenatal hydronephrosis.3 We examine some of the most common obstructive uropathies in neonates.
URETEROPELVIC JUNCTION OBSTRUCTION
Epidemiology
As the name suggests, UPJ obstruction is an obstruction in the urinary tract at the junction between the renal pelvis and the ureter. It is the most common cause of hydronephrosis in children. It can be seen in 1 in 1000–2000 neonates, with the majority of these diagnosed on prenatal ultrasound imaging of the fetus.4,5 In the neonatal period, UPJ obstruction has a 2:1 predominance in boys compared to girls; and left-sided to right-sided lesions are also more than 2:1 predominant in the neonatal period, approaching 67%. The reason for this is not entirely clear.6 It can be seen bilaterally in 10%–40% of neonatal presentations, although less than 5% of these patients will need bilateral repair.7 There is a hypothesis suggesting that multicystic dysplastic kidneys may result from early complete upper ureter or UPJ obstruction.
Pathophysiology
The etiology of UPJ obstruction is still debatable, and there are many theories regarding the pathophysiology. It can be described as an intrinsic defect in the UPJ that produces functional obstruction that results from poor ureter and renal pelvis smooth muscle activity.8 The development of fetal and rodent models of partial and complete UPJ obstruction has helped to shed more light on the pathophysiology.9,10 In experimental models, defects in the development of the smooth muscles have led to UPJ obstruction-induced hydronephrosis. Smooth muscle cell defects, as well as defects in the innervation of the renal pelvis and proximal ureter, can also be seen in human specimens obtained from patients who undergo pyeloplasty.11,12 Other mechanisms are anatomical anomalies, such as kinking of the UPJ from crossing vessels or even high insertion of the ureter into the renal pelvis.13 Sometimes, it is a combination of both mechanisms, but by and large, the exact mechanism is still being investigated.
Fetal and neonatal kidneys are still under significant growth and development; therefore, obstruction in the urinary tract can have deleterious effects. UPJ obstructions have been reported to lead to decreased nephrogenesis, manifesting from destruction of already-formed glomeruli, halting new glomeruli development,14,15 and phenotypic transformation of already-formed glomerular cells into mesenchymal cells.10,16 It promotes dilation, atrophy, apoptosis, and necrosis of the renal tubules.14,17–23 All of which leads to compensatory growth and hypertrophy of the nonobstructed contralateral kidney based on the degree and chronicity of the obstruction.24 In the fetus, due to the placenta being involved in exchange of nutrients and fetal blood filtration, the demand on renal function is much less than in the neonate25; therefore, the sequelae of renal failure may not be evident until the postpartum period. It has also been reported that if obstruction continues after birth, the neonatally obstructed kidney develops marked inflammatory infiltrates and, subsequently, increased fibrosis.26
Differential Diagnosis
Intuitively, because hydronephrosis is the most common finding in UPJ obstruction, the differential diagnosis usually includes most of the obstructive uropathies that can also present with unilateral or bilateral hydronephrosis. Some of these include nonpathologic extrarenal pelvis, multicystic dysplastic kidney, ureteral fibroepithelial polyps, ureteral valves, ureterovesical junction (UVJ) obstruction, VUR, ureteroceles, congenital megaureter and PUVs (usually if bilateral hydronephrosis is seen), among others.
Diagnostic Tests
Ultrasound
Pre- and postnatal ultrasounds are usually the first diagnostic imaging used to investigate neonatal obstructive uropathy. In utero, the second and third trimesters give the best estimate of the severity of postnatal hydronephrosis. The Society of Fetal Urology has a standardized grading system based on the anterior-pelvic (AP) diameter on the transverse plane of the renal pelvis. Dilation of 4–7 mm is considered mild, 7–10 mm is moderate, and greater than 10mm is severe hydronephrosis. Renal pelvis AP diameter greater than 15 mm in the third trimester has the highest risk of neonatal renal deterioration. When combined with findings of oligohydramnios and increased renal echogenicity, this was also highly predictive of urinary tract obstruction.27 Late gestational and postnatal hydronephrosis can be graded from grade I to grade IV.28 Grade I is mild dilation of the renal pelvis only, grade II is moderate dilation of the renal pelvis and a few calyces, grade III involves dilation of the renal pelvis with uniform dilation and visualization of all the calyces, and grade IV is a progression of grade III with evident thinning of the renal parenchyma.29
Prenatal and postnatal ultrasound offer the advantages of early detection of those cases of obstruction with potential postpartum health impact by identifying cases that will require further antenatal and postnatal evaluation. It helps limit the use of ionizing radiographic studies and can help mitigate parental distress and encourage timely referral to a pediatric urologist if possible interventions are needed to minimize adverse outcomes. Ideally, the first postnatal sonogram should be done at day of life 3 because of the physiologic oliguria that is experienced in neonates in the first 48 hours of life. This can temporarily decrease the dilation of the collecting system and give a false negative, especially if the hydronephrosis is not severe. If a negative study is obtained or only grade I to II hydronephrosis is seen, then repeating the ultrasound in 4–6 weeks is recommended for follow-up as this may remain normal or spontaneously resolve. If grade III–IV hydronephrosis is present, a more urgent workup and referral to a pediatric urologist is warranted.
Voiding Cystourethrogram
In neonates diagnosed with persistent hydronephrosis postpartum, voiding cystourethrogram (VCUG) is generally recommended. The American Urological Association (AUA) guidelines state that a VCUG should be done for children with grades 3 and 4 hydronephrosis, hydroureter, or an abnormal bladder on late-term prenatal or postnatal ultrasound or those neonates who develop a UTI postnatally while under observation.30 In cases of low-grade hydronephrosis (grades I and II), a VCUG need not be done, and observation of the neonate with ultrasound alone is acceptable. When recommended, a VCUG can be obtained within the first few days of life, prior to discharge from the hospital. The fluoroscopic VCUG is preferred as it provides the physician with the grade of the VUR and details of any anomalies within the bladder or urethra. The radionuclear VCUG has the advantage of exposing the infant to less radiation: 1 to 5 mrad in radionuclear VCUG vs 27 to 1000 mrad in fluoroscopic VCUG, although more recent studies report doses as low as 1.7 to 5.2 mrad with the fluoroscopic VCUG utilizing digital equipment.31 The radionuclear VCUG has more sensitivity in detecting VUR; however, it only answers whether there is reflux, but not the grade of vesicourethral reflux. Therefore, the nuclear VCUG would not be the imaging test of choice for the initial study given the desire to both grade the reflux and visualize any anatomic pathology. Fluoroscopic VCUGs can also be used to diagnose ureteroceles, ectopic ureter insertions, bladder diverticula, PUVs, among other neonatal genitourinary anomalies.
Diuretic Renogram
Due to immaturity of the neonatal kidneys, the best time to do a diuretic renogram is at 4 to 6 weeks after birth. The technetium 99 mercapto acetyl triglycine (99mTc MAG-3) renal scan done with Lasix is frequently used to assess renal perfusion, differential function, drainage, and the site of obstruction in the collecting system (UPJ vs UVJ). If differential function is normal and obstruction is mild, then the child can be observed with serial imaging until a time when spontaneous resolution is documented. If differential function of a kidney is diminished and high-grade obstruction is documented, then intervention may be required.
Computed Tomography–Intravenous Pyelogram
Computed tomography (CT)–intravenous pyelogram is not routinely used in the neonatal period for diagnosing obstruction in the urinary tract. This is due to the high amount of ionizing radiation associated with this study. Magnetic resonance imaging (MRI) under sedation is rapidly becoming the preferred anatomical and functional study of choice in the case of severe hydronephrosis.
Magnetic Resonance Urethrogram
Although the magnetic resonance urethrogram requires some degree of anesthetic sedation to keep the infant still during the image acquisition, it offers the advantage of not exposing the neonate to ionizing radiation and is able to dynamically assess renal parenchymal signal intensity changes deduced from the perfusion, filtration, and concentration of contrast. Compared to CT scan and renal scan, it has inherent superior contrast and spatial and temporal resolution.32 We are able to assess both anatomic and functional information from this study. The study provides us with differential renal function. In addition to detecting hydronephrosis, it can diagnose the location and possible cause of obstruction within the collecting system (ie, ureteral kinking, aberrant vessels, strictures). Based on the quality of the renal parenchyma and the degree of preoperative uropathy, MRU can provide some prognostic information for the surgeon32 and help guide the type and timing of intervention.
Management
One of the first things to determine in neonates with urinary tract obstruction is whether antibiotic prophylaxis is needed. The AUA 2010 guidelines recommended that in grade I to II hydronephrosis, no antibiotic prophylaxis is immediately needed unless the patient develops a UTI while being observed.30 In the first 3 months, penicillins or first-generation cephalosporins are recommended for UTI prophylaxis, but after that nitrofurantoin or trimethoprim/sulfamethoxazole can be used. A quarter of the standard antibiotic treatment dose given once nightly is preferred for UTI prophylaxis.
Timing for optimal surgical intervention is still an issue of controversy as there are currently no effective markers for determining the degree and progressive uropathic potential of various degrees of urinary tract obstruction.10,33 Pediatric urology experts advocate close follow-up, and it is recommended that intervention is warranted if there is continued compromise in renal function or progressive hydronephrosis.34–37 It is estimated that 25%–50% of the children diagnosed with prenatal hydronephrosis will eventually need some kind of surgical intervention.38,39
In neonates with solitary kidneys, severe bilateral hydronephrosis, and renal function compromise, early workup plus prophylactic antibiotics and surgical intervention are usually indicated. For those under observation, repeat imaging as appropriate (sonogram, renogram, and VCUG) in 3, 6, or 12 months can help determine improvement, stability, or progressive deterioration, which will dictate whether to follow the path of continued observation or surgical repair. Occasionally, when there is severe hydronephrosis and suggestion of significant renal functional compromise, percutaneous drainage of the affected kidney for a few weeks and repeating the renogram may help give a better idea of the actual renal function. This may provide useful information regarding whether repair of the obstruction or removal of the kidney is the preferred surgical strategy.
Outcomes and Follow-up
Despite appropriate surgical intervention, studies have shown that UPJ obstruction can result in permanent modifications to the renal parenchyma.40 Although studies looking at long-term postsurgical outcomes following repair of UPJ obstruction are limited, reports have shown that the reoperation rate can be up to 5%, and in some cases renal function improvement can be seen over time.41,42
RETROCAVAL URETER
Retrocaval ureter is a rare phenomenon that happens when the ureter travels posterior to the inferior vena cava (IVC). The embryologic event that precipitates it is the abnormal persistence of the subcardinal vein on the right side.43 It is typically characterized by an S-shaped deformity on intravenous or retrograde pyelography. It can also be detected on CT. The IVC can result in extrinsic compression of the ureter, which may cause significant obstruction. The ureter is usually medially deviated around the area of the third lumbar vertebra. It usually becomes symptomatic in the third to fourth decade of life; however, there have been rare case reports in neonates.44
It is corrected surgically like a UPJ obstruction by performing a dismembered pyeloplasty. This involves transection of the ureter above the IVC and moving and reanastomosing the proximal and distal ureter end anterior to the vena cava.45
VESICOURETERAL REFLUX
Epidemiology
Vesicoureteral reflux is the retrograde flow of urine from the bladder into the upper urinary tract. It can be seen in about 1% of neonates and up to 30%–45% of children who are diagnosed with a UTI.46–48 Statistically, 10%–15% of infants found to have UPJ obstruction do have ipsilateral VUR, hence the need to rule this out in neonates being worked up for UPJ obstruction. Girls are 2 times more likely to have VUR, although in patients who present with antenatal hydronephrosis, there tends to be a male predominance. Blacks are also more likely to have low-grade reflux as compared to Caucasian children, who have higher-grade and 3 times more VUR. Children younger than 2 years are also more likely to have VUR. There is about a 27% prevalence rate among siblings, and that rate is 36% for children with an affected parent. Among identical twins, there is up to 80% concordance as compared to 35% in fraternal twins.30,49–50
Pathophysiology
Primary VUR is most commonly due to an intrinsic defect in the vesicoureteral junction from improper insertion (ie, ectopic ureter insertion or inadequate tunneling of the intravesical ureter), leading to a loss of the natural antireflux mechanism. As the bladder fills with urine, the detrusor muscles compress and seal off the intravesical ureter, thereby preventing urine from refluxing backward into the ureter from the bladder. Secondary VUR can also result from anatomic defects (ie, PUVs or neurogenic bladder) affecting urine flow out of the bladder. According to the International Reflux Study Group (IRSG) who developed a classification system, VUR is classified based on the degree of retrograde filling of the ureter, calyceal and ureteral dilation seen on VCUG. Grade I involves reflux into the ureter without dilation. Grade II also is without dilation, but the urine fills retrograde into the renal collecting system. In grade III VUR, there is mild dilation of the ureter and the collecting system with mild blunting of the calyces. Grade IV shows gross dilation and tortuosity of the ureter and the collecting system with blunting of the calyces, while grade V is the most severe, with urine reflux grossly dilating the collecting system, severe tortuosity of the ureter, blunting of all the calyces with a loss of papillary impression and cortical thinning.51 Grades I and II are considered mild VUR, grade III is moderate VUR, and grade IV and V are severe VUR.
Differential Diagnosis
Some differential diagnoses to consider include UVJ obstruction, ureteroceles, congenital megaureter, PUVs, urethral atresia, and PBS.
Diagnostic Tests
Workup for VUR is usually prompted by the prenatal screening ultrasound finding of hydronephrosis. In neonates in whom prenatal hydronephrosis is missed, febrile UTI may be the reason to consider an infant has VUR. VUR is primarily diagnosed when reflux can be demonstrated on either fluoroscopic or radionuclear VCUG.
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