Urine in PET studies

Urinary system consists of the kidneys, ureters, urinary bladder, and urethra. Excess water and water-soluble waste products of metabolism are mainly excreted into urine, and partly by sweating. The liver can process and excrete waste products into the bile and faeces. Water content of urine is >90%, and urea (∼10-20 g/mL) is the largest constituent of solids. Protein content is normally very low, <10 mg/dL. Specific gravity of urine depends on the water balance, but is normally 1.000-1.040 g/mL. Normal range for pH in urine sample is 4-8; pH >6 favours bacterial growth, and bacterial growth tends to increase urine pH.

Urinary excretion

Urine is formed by renal filtration and tubular reabsorption and secretion. Adult humans produce daily ∼0.6-2.0 L urine, or 0.5-1.5 mL/(kg*h).

Assessing urinary excretion

Urinary excretion of radioactivity at certain time point can be calculated from the PET image, if urinary bladder is located in the field-of-view, and volume of the bladder can be measured from the PET image by contouring, or from anatomical CT or MR image taken at about the same time; using anatomical image from another time may cause bias, because bladder volume increases markedly during a dynamic PET scan (Bretin et al., 2017). Radioactivity concentration in the urine inside bladder is determined from a ROI drawn on the centre of the bladder. Radioactivity concentration, decay-corrected to the administration time, is then multiplied by the volume of urine in the bladder, and divided by the administered dose.

If bladder is voided before PET scan, the radioactivity concentration of urine sample must also be measured, corrected to the radioligand administration time, multiplied by urine volume, and added to the radioactivity remaining in the bladder.

Urinary excretion is often measured from urine samples only, preferably by summing the radioactivities from early and late samples. After voiding, the amount of radioactivity remaining in the bladder is relatively low (Jones et al., 1982), though the post-void residual volume is increased by age and in men with enlarged prostate.

Urine production rate (mL/min) can be estimated from the time between two voids and the volume of the second void, assuming that the residual volume in the bladder is the same for each void. The urine production rate and void volumes can be used to estimate the urine volume in the bladder at radioligand administration time (Dowd et al., 1991). For a radioligand that is excreted in its native form, we can assume that the activity of urine in the bladder (without voiding) has the same shape as the integral of the plasma time-activity curve, except for the distortion caused by delay and dispersion. If plasma time-activity curve (TAC) can be described with function f(t) consisting of the sum of three decaying exponentials, then the urine TAC can be represented as its integral g(t) (Dowd et al., 1991):

$\begin{equation} f(t) = A e^{-\lambda_1 t} + B e^{-\lambda_2 t} + C e^{-\lambda_3 t} \end{equation}$ $\begin{equation} g(t) = \frac{A}{\lambda_1}(1 - e^{-\lambda_1 t}) + \frac{B}{\lambda_2}(1 - e^{-\lambda_2 t}) + \frac{C}{\lambda_3}(1 - e^{-\lambda_3 t}) \end{equation}$

A four-exponential function with a pair of repeated eigenvalues describes plasma TAC better, including the ascending phase, and thus its integral may better fit the initial part of urine TAC:

$\begin{equation} f(t) = (A \: t - B - C) e^{-\lambda_1 t} + B e^{-\lambda_2 t} + C e^{-\lambda_3 t} \end{equation}$ $\begin{equation} g(t) = \small{\frac{A_1 - \lambda_1 (A_2 + A_3)}{\lambda_1^2}} (1 - e^{-\lambda_1 t}) \ - \frac{A_1}{\lambda_1} \: t \: e^{-\lambda_1 t} \ + \frac{A_2}{\lambda_2} (1 - e^{-\lambda_2 t}) + \frac{A_3}{\lambda_3} (1 - e^{-\lambda_3 t}) \end{equation}$

Kinetics of radioactivity in the bladder can be used in deriving input function in small animal FDG PET studies (Wong et al., 2013).

Urinary clearance

Urinary clearance (CL_U ) of a drug or radiopharmaceutical is the virtual volume of plasma from which drug is excreted to urine per unit time. Urinary clearance can be calculated from the cumulative amount of drug excreted unchanged in the urine (A_U ) up to time T and the AUC of the plasma drug concentration (Tucker, 1981):

$\begin{equation} CL_U = \frac{A_U(T)}{AUC_{0-T}} \end{equation}$

Similarly, the urinary clearance of a radiopharmaceutical can be defined as (metabolite corrected) radioactivity in the urine (or bladder in the PET image) divided by the AUC of blood (or plasma) curve. Since the blood curve is used, the result is independent on other clearance routes, including uptake of radiopharmaceutical in the tissues.

Kidney function is commonly assessed by measuring renal plasma clearance of exogenous or endogenous markers of glomerular and tubular filtration. Glomerular filtration rate (GFR) can be measured using markers that are not secreted or reabsorbed by the tubular system. Urinary clearance considers only the marker entering the urine, while renal plasma clearance includes also the possible renal retention of the marker. Urinary clearance can be higher than GFR if the drug undergoes tubular secretion (Peters, 1998).

Kidney function

Glomerular filtration rate is used as an index of kidney function (renal function). Radioligands that are not protein bound in the blood, and are not reabsorbed, secreted, or metabolized in the renal tubular system, can be used to directly measure GFR. Error prone urinary collection can then be avoided, as renal plasma clearance and urinary clearance are equal, and GFR can be calculated from a few plasma samples. Alternatively, ROIs drawn on the bladder, ureters, and kidneys can be used (Hofman et al., 2015).

Several PET tracers for measuring GFR have been introduced, including [⁶⁸Ga]DOTA and [⁶⁸Ga]EDTA. Urinary clearance of [¹⁸F]fluoride has been used in rats to assess renal function noninvasively, with ROIs drawn on the heart cavity and urinary bladder. The results correlated with traditional GFR estimation methods, even with variable urine pH (Schnöckel et al., 2008). In humans, tubular reabsorption of [¹⁸F]F^- is increased (renal clearance is reduced) with decreased urine flow (Park-Holohan et al, 2001), suggesting that the method may not be reliable for estimating renal function in humans.

Radiation dose

Radioligand and/or its radiometabolites are often excreted into urine, which leads to relatively high radiation dose to the urinary bladder and reduces the image quality in the pelvic region. In clinical imaging, especially in oncology, a whole-body scan is started only after a certain waiting period (late-scan); bladder voiding before the delayed scan can markedly improve the image quality and reduce the radiation dose to the patient and staff conducting the study. Bladder catheterization would be effective but impractical way to improve image quality.

The dosimetry of radiopharmaceuticals requires that the urine is collected until its radioactivity is negligible. The urine volume V_U and radioactivity of a sample of urine A_U(t_m) are measured, and the time of radioactivity measurement t_m is recorded. Radioactivity concentration in the urine, C_U(t_m) , is calculated by dividing the sample radioactivity minus background radioactivity A_BKG by the sample volume V_S :

$\begin{equation} C_{U}(t_{m}) = \frac{A_{U}(t_{m}) - A_{BKG}}{V_S} \end{equation}$

Radioactivity concentration in the urine sample is then decay-corrected to the administration time of the radiopharmaceutical, t_a :

$\begin{equation} C_{U}(t_{a}) = C_{U}(t_{m}) \times e^{ln(2) \times \frac{t_m - t_{a}}{T_{1/2}}} \end{equation}$

The times, including the half-life of the isotope T_1/2 , must be given in the same units, usually minutes. Now, the total decay-corrected radioactivity in the urine can be calculated by multiplying the concentration with the urine volume. Dividing this by the administered radioactivity A_A gives the fraction of dose excreted into urine, f_U :

$\begin{equation} f_{U} = \frac{V_U \times C_{U}(t_{a})}{A_A} \end{equation}$

All the equations combined, percentage of radioactivity excreted into urine can be calculated as:

$\begin{equation} \frac{A_{U}(t_{m})}{A_A} \times \frac{V_U}{V_S} \times e^{ln(2) \times \frac{t_m - t_{a}}{T_{1/2}}} \times 100\% \end{equation}$

This calculation needs to be done for each voiding, and the percentages are then added up.

FDG

Mean percentages of FDG excreted into urine were 13±1% and 21±5% of injected dose 1 and 2 hours after FDG administration, respectively (Mejia et al., 1991). Urinary excretion of FDG is highly variable. Bach-Gansmo et al (2012) reported that excretion at mean latency time of 71 min was 2-20% of the injected dose, with an average of ∼10%. FDG excretion is somewhat higher in hydrated than dehydrated subjects, 17 versus 14% of injected dose 150 min after FDG administration (Moran et al., 1999). With strict water drinking and voiding schedule, two hours after FDG administration, 21±3% of injected dose was excreted into urine (Jones et al., 1982).

Early and frequent bladder voiding reduces radiation dose considerably (Hays & Segall, 1998). If the voiding time is changed from 2 h to 1 h after FDG administration, the radiation dose of bladder wall reduces by 50% (Jones et al., 1982). To minimize the dose to the bladder wall, the bladder should be as full as possible at the time of FDG administration (Dowd et al., 1991; Thomas et al., 1999). Hydration or administration of diuretics, such as furosemide, is recommended also in order to improve image contrast between urine and tumours in the pelvic area (Boellaard et al., 2015).

Literature

Garbarino S, Caviglia G, Sambuceti G, Benvenuto F, Piana M. A novel description of FDG excretion in the renal system: application to metformin-treated models. Phys Med Biol. 2014; 59(10): 2469-2484. doi: 10.1088/0031-9155/59/10/2469.

Schnöckel U, Reuter S, Stegger L, Schlatter E, Schäfers KP, Hermann S, Schober O, Gabriëls G, Schäfers M. Dynamic ¹⁸F-fluoride small animal PET to noninvasively assess renal function in rats. Eur J Nucl Med Mol Imaging 2008; 35: 2267-2274. doi: 10.1007/s00259-008-0878-y.

Ridley JW: Fundamentals of the Study of Urine and Body Fluids. Springer, 2018. doi: 10.1007/978-3-319-78417-5.

Tucker GT. Measurement of the renal clearance of drugs. Br J clin Pharmac. 1981; 12: 761-779. doi: 10.1111/j.1365-2125.1981.tb01304.x.

Tags: Urinary bladder, Kidney, FDG, Exponential function, Pharmacokinetics, Clearance

Updated at: 2021-04-06
Created at: 2018-10-05
Written by: Vesa Oikonen, Tuula Tolvanen