Radionuclide Cystography

Anatomy and Physiology

The fundamental anatomy in performing radionuclide cystography (RNC) includes the kidneys, ureters, bladder, and urethra. The resolution of modern gamma cameras is as low as several millimeters to nearly a centimeter; thus, structures that are smaller than this resolution limit are not detectable during RNC. Typically, the kidneys excrete urine into the renal pelvis, which then drains into the ureter at the ureteropelvic junction (UPJ). The ureters are paired structures that contain a muscular layer in their walls along with a mucosal layer. This muscular layer intermittently contracts, which results in a wave-like contraction running from the UPJ to its connection with the bladder, known as the ureterovesical junction (UVJ); these contractions, along with the assistance of gravity, help propel urine forward and into the bladder. At the insertion into the bladder, the ureters traverse the bladder wall's posterolateral aspect in an oblique orientation. This key anatomic relationship allows for a one-way passage from the ureters into the bladder.[1] When this anatomic relationship is altered, the UVJ valve becomes compromised, and reflux of urine into the ureters can result, known as vesicoureteric reflux (VUR). VUR is a common finding in children, and early diagnosis is necessary to prevent progressive renal damage.

When the bladder is filled with urine, sensory nerves initiate a reflex arc called the micturition reflex. This launches a series of events that include bladder wall contraction by the detrusor muscle and relaxation of the internal urethral sphincter at the bladder neck. Urine voiding is controlled voluntarily by contraction or relaxation of the external urethral sphincter.[2]

For the usual retrograde RNC examination, there is a clear delineation of the urinary bladder's architecture, which should be mostly round with a possible slight V-shaped taper towards its base. The paired ureters insert posterolaterally into the bladder, and if reflux is present, these are seen as thin curvilinear extensions of increased radiotracer activity running superiorly to the renal pelvis. In cases of severe or chronic reflux, the ureters may dilate and become more tortuous. If increased activity is present outside the expected region of the bladder or ureters or if there is an unexpected deformity of the bladder contour, correlation with other imaging or non-imaging procedures may be necessary to exclude intrinsic lesions such as bladder diverticula or extrinsic compression by adjacent structures.

RNC is also frequently performed in the setting of a prior renal transplant. It is important to note that most transplanted kidneys are placed within the pelvis and are anastomosed to the iliac vessels. The transplanted organ in this region results in an expected extrinsic compressive deformity on the appearance of the bladder during RNC. Urinary reflux is a common finding in renal transplants given the absence of the standard UVJ valve in these cases.

Indications

Common indications for performing radionuclide cystography (RNC) are listed below:[3]

1. Initial evaluation for vesicoureteric reflux (VUR) in female patients with urinary tract infection
2. Diagnosis of VUR in children with a family history of VUR
3. Follow-up assessment of VUR following medical or surgical management
4. Evaluation for reflux in the setting of a neurogenic bladder
5. Diagnosis of VUR in renal transplant recipients
6. Diagnosis and follow-up of VUR in patients with persistent prenatal hydronephrosis
7. Quantification of postvoid residual urine in the bladder

Contraindications

There are few absolute contraindications to radionuclide cystography (RNC), given that it is a safe and well-tolerated procedure. Several contraindications are listed below:

1. Allergy or history of an adverse event with prior radiopharmaceutical administration: This is an infrequent occurrence. Life-threatening episodes with radiopharmaceuticals are infrequent. Adverse reactions are mostly allergic and sometimes include vasovagal reactions.[4]
2. Active or untreated urinary tract infection: If sodium pertechnetate is administered (further discussed below), systemic absorption can occur in inflammation.[5]

There are multiple additional considerations before performing RNC, although none are absolute contraindications to performing this procedure. Clinical judgment and modifications may be necessary to ensure a diagnostic-quality examination. 

1. Pregnancy- The whole fetus radiation dose during RNC is below 5 mGy, far below the known deterministic fetal threshold. In the setting of known pregnancy, alternative studies such as contrast-enhanced ultrasound should be performed. If no alternatives are available, the radionuclide dose should be kept as low as reasonably possible without sacrificing the study's diagnostic quality.[6][7]
2. Genitourinary Anatomic Anomalies- Deferral of RNC should be considered if known urethral abnormalities could result in either entrapment of radiopharmaceutical into the bladder vagina, rectum, or elsewhere. Similarly, since a urethral or conduit catheter is used during RNC, special attention should be paid toward abnormalities resulting in substantial leakage or loss of the radiopharmaceutical. Special care might be necessary to minimize radiopharmaceutical contamination.
3. Patient Participation- The most effective RNC examinations use active patient participation, specifically during the study's active voiding portions. There are circumstances where VUR is only present during micturition, and if the patient cannot participate, the negative study may be falsely reassuring.

Equipment

Essential equipment and supplies for radionuclide cystography (RNC) are:

1. Equipment for foley catheterization and installing the radiopharmaceutical into the bladder (if a retrograde examination is performed). Latex materials should be avoided to prevent the development of hypersensitivity disorders.
2. Radiopharmaceutical (discussed below)
3. Sterile saline
4. Gamma camera with low-energy all-purpose (LEAP) or high-resolution collimator. Magnification views may be necessary for children.
5. Equipment for storage, collection, disposal, and decontamination of the contaminated urine and other materials is necessary and must comply with local regulations.

Radiopharmaceuticals

The radiopharmaceuticals used in retrograde RNC are: technetium-99m (Tc-99m) sodium pertechnetate, Tc-99m sulfur colloid, or Tc-99m diethylenetriamine penta-acetic acid (DTPA). The administered dose is 0.2-1 mCi. The administered activity should not exceed 1 mCi for each cycle of voiding in pediatric patients. Sodium pertechnetate should be avoided in patients with surgical neobladders (if gastric or intestinal tissues are used for bladder augmentation), as sodium pertechnetate avidly binds gastrointestinal tissue.[8] Similarly, pertechnetate should be avoided in the inflammation setting, since this may result in systemic absorption of the radiopharmaceutical with subsequent excretion by the kidneys, potentially causing erroneous results.[5]

In antegrade RNC, radiopharmaceuticals are administered intravenously, excreted into the urinary tract via the kidneys. This method avoids bladder catheterization and allows for the relative assessment of renal excretory function. The radiopharmaceuticals most commonly used for the antegrade technique include technetium-99m-mercaptoacetyltriglycine (Tc-99m-MAG3) or technetium-99m-diethylenetriaminepentaacetic acid (Tc-99m-DTPA). The minimal administered activity for each of these radiopharmaceuticals is 0.5 mCi.[9]

Technetium-99 emits photons, which are detected by the gamma camera. To ensure sufficient photons to generate an image, the technetium-99m activity must be checked before administration. This activity can be measured based on the number of disintegrations that occur per second, which correspond to the number of photons emitted. These disintegrations are measured using the becquerel (Bq), equivalent to one disintegration per second. The minimal activity for technetium-99m-pertechnetate for RNC is 0.5 to 1.0mCi.[9]

Gamma Camera

A gamma camera is a specialized piece of equipment used to image gamma radiation, a process that is also called scintigraphy. This equipment's basic components include a collimator, a large sodium-iodide (NaI) crystal, multiple photomultiplier tubes, and image processing electronics. The collimator absorbs scattered gamma rays, thereby increasing the resolution of the camera. The NaI crystal absorbs the gamma photons and scintillates. This flash of light that is produced is detected by the photomultipliers, which sends the count to the computer, which reconstructs a two-dimensional image. The attached computer is also used to post-process the images. A further discussion on the physics and applications of gamma cameras can be found elsewhere.[10]

Technique or Treatment

Before any examination, a thorough explanation of the procedure to the patient or parents in a minor setting is necessary. A comprehensive medical and surgical history is essential to understand the exam indications fully, rule out concurrent urinary tract infection, and delineate any prior surgical procedures on the genitourinary tract. Previous radiologic exams should be reviewed for pertinent anatomic considerations or other findings.

For the retrograde radionuclide cystography (RNC) exam, a foley catheter is first inserted into the bladder using an aseptic technique. In certain scenarios, a suprapubic puncture may also be considered.[11] After obtaining access to the bladder, the patient is placed in a seated position over a bedpan, if possible, with the gamma camera detector positioned behind the patient. If patient cooperation precludes an upright position, supine imaging can be performed. Next, the radiopharmaceutical is injected into the bladder; this is performed either by mixing the radiopharmaceutical with normal saline (250-500mL) or by directly injecting the radiopharmaceutical into the catheter followed by saline. If the latter approach is taken, 10-20mL of normal saline should be injected into the catheter before radiopharmaceutical administration to prevent direct exposure of the bladder mucosa to the technetium-99m.[3] 

The bladder is instilled until it reaches its full capacity, determined either by the cessation of passive gravity flow or by reaching the appropriate urinary volume for the patient's age.[3] The bladder volume in children is approximated by the formula (in milliliters): [age (years) + 2] x 30mL.[12] Adult bladder capacity can range from 300 to 400mL.[13] Slowly filling the bladder can decrease bladder spasm, and using body temperature saline can improve patient comfort.

Any radioactivity seen above the dome of the bladder or within the renal collecting system indicates VUR. VUR can occur during, before, or after voiding. RNC is very sensitive to identifying reflux. It can detect reflux volume as low as 1 ml. If no activity is seen above the bladder, images are obtained during voiding, as VUR may only be observed during this phase of the examination. Routinely, 5-second images are acquired during filling and voiding with 30-second anterior pre and postvoid images. For reporting purposes, VUR on RNC is graded as mild, moderate, or severe:

• Mild- reflux confined to the ureter
• Moderate: reflux up to the pelvicalyceal system
• Severe: reflux up to the pelvicalyceal system associated with a dilated collecting system along with a dilated and tortuous ureter

Antegrade RNC is performed by first obtaining intravenous access and injecting the appropriate radiopharmaceutical. Supine images of the kidneys and renal collecting system are obtained, and the bladder is imaged until it reaches its maximum capacity. Like the retrograde technique, if possible, the patient is placed in the upright position to void images with the gamma camera at their back. If the patient is not able to cooperate, images are obtained in the supine position. Failure of a patient to hold their urine until requested can result in a nondiagnostic study.[9]

Residual bladder postvoid volume is measured by drawing region of interest (ROI) over the bladder on pre and postvoid images.[3]

Residual volume = [voided volume in ml X postvoid bladder counts (ROI)]/[ Initial bladder counts (ROI)- postvoid bladder counts (ROI)]

Complications

Complications are rare when performing radionuclide cystography (RNC). However, there is always a risk of iatrogenic urinary tract infections when urethral catheterization is performed. A recent study demonstrated a 1% incidence of UTI following a retrograde RNC, which occurred in the setting of pre-existing urologic abnormalities such as VUR or hydronephrosis.[14] Given this low risk, periprocedural antibiotics are not routinely recommended. Minor complications, such as urethral trauma, may also occur.

Clinical Significance

Early and accurate diagnosis of vesicoureteral reflux (VUR) is essential to prevent chronic renal damage associated with urinary reflux. Since VUR is commonly diagnosed in childhood and often requires multiple follow-up examinations, minimizing radiation exposure is of great importance to reduce both the stochastic and deterministic effects of ionizing radiation. The two most common radiologic procedures used to diagnose VUR include radionuclide cystography (RNC) and conventional fluoroscopic contrast-enhanced micturating cystourethrograms (MCU). MCU utilizes x-rays to view iodinated contrast instilled into the bladder via a catheter. Then a combination of still and cine images are acquired using fluoroscopy. Both X-rays and gamma rays are forms of ionizing radiation that can cause direct and indirect DNA damage. When comparing RNC and MCU, RNC is not only more sensitive in detecting VUR, but it uses approximately 1/20th of the overall radiation dose.[15] 

To give perspective, the RNC effective dose is 0.0024 mSv, which is nearly ten times lower than that of a posterior-anterior (PA) chest radiograph, which is approximately 0.02 mSv.[16] The mean effective dose for MCU ranges from 0.03 to 0.4 mSv.[17] Novel modalities such as contrast-enhanced voiding urosonography (ceVUS) have the advantage of not requiring ionizing radiation.[18] Rather, ceVUS utilizes high-frequency sound waves (ultrasound) combined with a sonographic contrast agent to obtain high-quality images of the bladder, urethra, and ureters. However, this technique may be difficult to perform in certain uncommon pathologic conditions, is technique-dependent, and subject to limitations by overlying bowel gas, which can hamper ultrasound transmission.[18] As such, RNC may be the exam of choice in certain scenarios. The accurate and safe performance of RNC is critical for detecting genitourinary pathology and minimizing risks.

Enhancing Healthcare Team Outcomes

Safely and accurately performing radionuclide cystography (RNC) depends on a multidisciplinary team. Nuclear medicine providers must thoroughly review each case to understand the indications and determine the adequate dosing. Nuclear medicine technicians and pharmacists are responsible for assuring the purity and activity of the radiopharmaceuticals that are employed; this is critical to not only ensure adequate gamma camera counts and diagnostic accuracy but also for patient safety. Institutional radiation safety officers are required by the Nuclear Regulatory Commission to oversee any institutions that use radioactive materials, and this is to ensure the safety of the patients, staff, and community.[19] 

Urologists, nephrologists, pediatricians, and family providers make up most providers that order RNC examinations; effective communication with these ordering providers ensures the appropriate use of RNC and provides key context for the diagnostician. Together this multidisciplinary team offers indispensable value in both safety and efficacy when performing RNC.