US Pharm. 2016;41(5):HS2-HS6.
ABSTRACT: Antenatal hydronephrosis (ANH) is one of the most common anomalies identified during routine prenatal ultrasonography. Most of the time ANH is self-limiting, but it can also be an indication of underlying urologic pathology. Complications associated with ANH include increased risk of urinary tract infection and decreased renal function. Risk factors that increase the likelihood of complications include a high value for anteroposterior diameter, female gender, the lack of circumcision in males, and the presence of reflux or obstruction. The use of antibiotic prophylaxis in patients with ANH is debatable, but the presence of certain risk factors can help the pharmacist determine the appropriateness of antibiotic use in patients.
Hydronephrosis, a condition defined by the distention and dilation of the renal pelvis and calyces, is one of the most common anomalies identified during prenatal ultrasonography. It is estimated that hydronephrosis affects from 1% to 5% of all pregnancies.1 The condition is most commonly diagnosed before birth (antenatal hydronephrosis [ANH]), but it can also be diagnosed after birth (postnatal hydronephrosis). The goal of prenatal diagnosis is to identify cases that may benefit from possible early interventions while minimizing adverse outcomes. Approximately 20% to 40% of ANH cases are bilateral, with boys twice as likely as girls to be affected.2 The majority of cases (48%-80%) are mild and are caused by transient dilations of the collecting system that resolve as the fetus matures.1,2-4 Two of the most common causes of ANH—vesicoureteral reflux (VUR) and ureteropelvic junction obstruction (UPJO)—occur at an incidence of approximately 10% to 20% and may increase the risk of postnatal complications.1 Complications associated with increased severity or late diagnosis include a high risk of urinary tract infections (UTIs) and renal dysfunction. This article gives an overview of hydronephrosis and discusses the role of pharmacists in optimizing the management of ANH, especially in patients at increased risk for complications.
Grading of ANH
The Society of Fetal Urology (SFU) developed a grading system based on the degree of pelvic dilation, the presence of calyceal dilation, and the presence and severity of parenchymal thinning or atrophy.5 The grades range from 0 to IV; a grade of 0 denotes a normal examination without pelvic dilation, whereas grade IV indicates dilation of both the renal pelvis and the calyces and thinning of the renal parenchyma. Low-grade hydronephrosis typically refers to an SFU grade of I or II, and high-grade hydronephrosis refers to an SFU grade of III or IV.
In 2014, a multidisciplinary panel of specialists proposed a urinary tract dilation classification system in an effort to provide a standardized scheme for perinatal evaluation based on sonographic criteria.6 The proposed classification system is based on anteroposterior dilation (APD) of the renal pelvis, calyceal dilation, bladder abnormalities, ureteral abnormalities, and renal parenchymal thickness and appearance. The findings are graded on a scale of 1 to 3, with 3 being the most severe. Studies validating this classification system are sparse, and the system’s utility in predicting clinically significant outcomes has yet to be determined.
Predictors of Postnatal Pathology
Although most cases of ANH are self-limiting, a finding of ANH during routine pregnancy ultrasound may indicate the presence of urinary tract pathology. Identifying the underlying etiology is imperative because specific causes are known to increase the severity of the condition. A meta-analysis found that patients with UPJO had a significant risk of pathology with increasing degrees of ANH.7 This risk was not identified in patients with VUR; however, VUR and UPJO can predispose patients to recurrent UTIs, which can result in complications such as renal scarring, abnormal renal development, and the risk of chronic kidney disease later in life.1,8-10
Another predictor of postnatal pathology is the degree of renal pelvic dilation according to the APD. In general, higher APD values are associated with a lower likelihood of spontaneous resolution, an increased risk of undesirable outcomes, and the need for surgical intervention.11,12 One study showed that APD cutoffs of 9.5 mm in the second trimester and 15 mm in the third trimester predicted an increased risk of neonatal urologic surgery.13 Similarly, an SFU grade of III or IV was identified as an independent risk factor for surgery and febrile UTIs.8,9,13
The prenatal appearance of the renal parenchyma is another predictor of postnatal pathology. The lack of a reniform shape, the presence of renal cysts, increased echogenicity, and parenchymal thinning are all indications that a closer evaluation of renal function is warranted.1,4,8 Other sonographic markers that increase the risk of adverse outcomes are bilateral ANH, bladder-wall thickening, ureteral dilation, and the presence of ureteroceles.1
The presence of oligohydramnios (deficiency in the amount of amniotic fluid) is a nonsonographic marker that may indicate posterior urethral valve dysfunction.14 The amniotic-fluid level is maintained primarily by fetal urine production beginning in the 16th week of development.1 A drop below 5 on the amniotic-fluid index may indicate an impairment in fetal renal function.4 Complications associated with posterior urethral valve dysfunction may include pulmonary hypoplasia and renal insufficiency.14
Prenatal Management
The goal of prenatal management is early identification of patients at risk for developing significant postnatal urologic pathologies. Parents of infants with these risk factors should be promptly referred to a pediatric urologist and provided with adequate counseling. Since the majority of ANH cases resolve during the pregnancy, a watch-and-wait approach may be preferred if no other risk factors are present. The SFU consensus recommends that a repeat ultrasound be performed in the third trimester depending on the severity of ANH, the presence of other risk factors, and gestational age at initial diagnosis.1 Options for severe cases include early delivery and surgical interventions such as fetal shunting in the case of amniotic-fluid anomaly.
Postnatal Management
A 2006 meta-analysis showed that the risk of any postnatal pathology per degree of ANH was 11.9% for mild ANH, 45.1% for moderate ANH, and 88.3% for severe ANH.7 These findings stress the importance of early and effective management. Determining the cause of ANH is imperative for establishing a treatment strategy and preventing unnecessary testing of the newborn. Adequate parental counseling is also important, as anxiety is understandably common during the treatment process.
The degree and severity of ANH largely dictate the extent of postnatal imaging. Ultrasound of the kidney and bladder is the most commonly used imaging modality owing to its ease of use, low cost, and absence of contrast or radiation exposure.1 However, the patient’s hydration status can largely impact the predictive value of the ultrasound, so it is important to note when the ultrasound was performed. Because infants are relatively dehydrated at birth, it is recommended that postnatal ultrasounds be conducted at least 48 hours after birth to ensure accurate results.1,4
Other commonly used imaging modalities are voiding cystourethrography (VCUG) and dynamic renal scintigraphy (DRS). VCUG is performed when visualization of the lower urinary tract is required, especially in ruling out VUR as a cause of ANH. DRS is used as an adjunct after other renal imaging modalities are performed to estimate differential renal function and determine the severity of obstruction.1 The radiopharmaceutical agent of choice for DRS is mercaptoacetyltriglycine (Tc-MAG3), which requires lower radiation doses and has a half-life of approximately 6 hours, thus minimizing the amount of radiation the patient is exposed to.1,15 Dimercaptosuccinic acid (DMSA) is another radiopharmaceutical agent that is used to visualize the renal parenchyma. DMSA binds tightly to the renal tubular cells and is primarily used for the evaluation of renal scars or renal dysplasia.1 It is important for pharmacists to be aware that a diuretic (most commonly furosemide) is typically given in conjunction with the radiopharmaceutical before a DRS procedure, and the protocol for administration can vary widely among institutions.
Surgical intervention is reserved for patients with severe risk factors that predispose them to a greater likelihood of complications. One study conducted in children with UPJO found that 50% of patients with such risk factors underwent surgery within the first 2 years of life, whereas most of the remaining patients underwent surgery at age 2 to 4 years.13 Circumcision is a low-risk option that can be considered for male infants to decrease the risk of febrile UTIs.8,9
Antibiotic Prophylaxis
One of the most widely discussed topics in the postnatal management of ANH is the initiation of continuous antibiotic prophylaxis (CAP). One study found that infants with ANH were nearly 12 times more likely to have pyelonephritis-related hospitalizations in the first year of life.16 The risks versus benefits of long-term antibiotics may not always be clear, but there are several factors that pharmacists should consider when evaluating the need for CAP.
The necessity of CAP depends on the presentation of several risk factors. Guidelines by the American Urological Association do not recommend CAP in patients with SFU grades I and II.17 One study found that patients with SFU grade I or II had resolution rates of 96.7% and 98.6%, respectively, and only 0.7% of patients experienced febrile UTI.3 Other studies have also demonstrated a low likelihood of UTI in mild ANH even in the presence of VUR or UPJO.18,19 Another study revealed that patients with low-grade hydronephrosis receiving CAP had similar UTI rates as those not receiving CAP.20 Therefore, the role of CAP is likely limited in patients with low-grade ANH.
Conversely, high-grade hydronephrosis is associated with a higher risk of UTIs. In one study, children with high-grade hydronephrosis who were treated with CAP had significantly lower rates of UTI compared with similar patients not receiving CAP (14.6% vs. 28.9%).20 Comparable results have been found in other studies evaluating the risk of febrile UTI in ANH.8,9,21 A Canadian economic analysis of CAP in this population found that CAP use reduced healthcare costs by C$385.25 over the course of 2 years, with a 0.21 reduction in the number of outpatient UTIs and a 0.04 reduction in UTIs requiring hospitalization.22 Therefore, the use of CAP may be a prudent consideration in patients with more severe ANH. Other risk factors that may increase the risk of UTIs are VUR and UPJO, especially in patients with a severe case of either disorder and bilaterally affected kidneys.8,9,21,23 Female gender and lack of circumcision in males are independent risk factors for febrile UTI.8-9,21
The ideal prophylactic antibiotic has a low serum concentration and high urine levels and provides broad-spectrum coverage.24 Trimethoprim-sulfamethoxazole (TMP-SMX) and nitrofurantoin are the preferred agents in children aged 2 months and older.14 Options for patients younger than 2 months of age include trimethoprim and amoxicillin.14 Because of increasing antimicrobial resistance to amoxicillin and ampicillin, use in children older than 2 months is not recommended.24 The recommended dosage for all agents is a quarter of the general dosing for susceptible infections, administered nightly (TABLE 1).25-28 The optimal duration of CAP is still widely debated, but in general prophylaxis must be continued until the resolution of risk factors, such as confirmed absence of VUR or other urologic pathology.
The Pharmacist’s Role
The pharmacist should be cognizant of the various factors that may increase the risk of complications in a patient with ANH. UTIs are a significant concern in patients with ANH, and the pharmacist can monitor the patient for the presence of infection as well as its resolution. Pharmacists should be aware of the patient-specific factors in which CAP may be beneficial, and they should provide patients with a timely suggestion regarding appropriate antibiotics. In addition, renal function should be monitored closely, including glomerular filtration rate, serum creatinine, and urine output. The dosing of medications may require adjustments based on renal function. The diagnostic tools used—such as contrast, Tc-MAG3, and DMSA—may exert adverse effects on renal function, which underscores the necessity for close monitoring of renal function and therapeutic monitoring of medications affected by compromised kidney function. Allergic reactions and antibiotic intolerance should be monitored, since many patients will receive prolonged exposure to these agents. Other aspects of pharmacotherapy that are beyond the scope of this article include pain management, fluid maintenance, and other supportive medications. Pharmacists are trained to manage all pharmacotherapies and, accordingly, should play an active role in the multidisciplinary management of patients with ANH.
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