Elevated ¹⁸F-FDG Levels in Blood and Organs After Angiotensin II Receptor Blocker Administration: Experiment in Mice Administered Telmisartan

DISCUSSION

In this study, we showed that telmisartan treatment dose-dependently increased plasma BUN and creatinine levels in mice and that the ¹⁸F-FDG level in the blood concomitantly increased (Supplemental Fig. 2). ¹⁸F-FDG level positively correlated with BUN and creatinine levels (Fig. 1). ¹⁸F-FDG levels in several organs were significantly higher in mice treated with moderate- and high-dose telmisartan (Fig. 2). Renal ¹⁸F-FDG excretion was attenuated by the telmisartan treatment (Fig. 3). Moreover, the results indicated that these parameters returned to baseline levels 3 wk after treatment cessation.

With the above-mentioned findings, we demonstrated that ARB treatment affected renal function and ¹⁸F-FDG uptake in the blood and organs of mice. In clinical settings, quantification of glucose metabolism by ¹⁸F-FDG PET is an established diagnostic technique. The levels of ¹⁸F-FDG uptake in target tissues provide important information for evaluating the malignancy of tumors and the viability of the myocardium and for identifying the location of seizure foci. In particular, as a semiquantitative parameter, SUV is widely used to evaluate tumor malignancy. Moreover, in recent years, the reproducibility of this semiquantitative measurement has been of great concern, and changes in SUV after therapy have been used to evaluate its efficacy (14). Therefore, such an effect of ARB treatment on renal function may consequently change SUV in ¹⁸F-FDG PET images and cause difficulties with diagnosis in clinical practice.

In agreement with our data, an increase in serum creatinine level after initiation of ACEI or ARB therapy was also commonly found in clinical trials, generally occurred within 2 wk, and was not associated with long-term harm (2). At the same time, ¹⁸F-FDG PET is also widely applied in oncology, cardiology, and neurology (6). There is a high probability that ¹⁸F-FDG PET was performed on patients receiving ARB or ACEI treatment. These lines of evidence suggest that the concomitant increase in blood ¹⁸F-FDG level may also be found in ARB- or ACEI-treated patients undergoing ¹⁸F-FDG PET.

From clinical data, the decrease in GFR associated with the initiation of renin angiotensin aldosterone system inhibition was reported to be reversible with discontinuation of ACEI or ARB therapy (15). In concordance with this observation, in the present study a brief discontinuation of ARB treatment reversed the ¹⁸F-FDG levels in the blood and organs to baseline levels (Fig. 2B) and reversed ¹⁸F-FDG excretion in the kidneys (Fig. 3). These findings indicate that a brief cessation of ARB treatment may be a potential method to avoid the effects of ARBs on ¹⁸F-FDG PET imaging in a clinical setting.

In the present study, we did not directly measure GFR in ARB-treated mice, but the elevated plasma creatinine levels in our mice indicate a decrease in GFR. The decreased GFR consequently may delay ¹⁸F-FDG elimination and result in high blood levels of ¹⁸F-FDG. As evidence of the close relationship between ¹⁸F-FDG excretion and renal function, in the present study the ¹⁸F-FDG level in the blood concomitantly changed with plasma BUN and creatinine levels (Supplemental Fig. 2) and correlated positively with plasma BUN (r = 0.48, P < 0.01) and creatinine levels (r = 0.61, P < 0.01) (Fig. 1).

In this study, serum creatinine levels were lower than 0.7 mg/dL even in mice treated with high-dose telmisartan. A creatinine level of 0.7 mg/dL is still within the reference range for mice. In patients, ARB or ACEI treatment increases the serum creatinine level to approximately 3 mg/dL (2), whereas the reference range for humans is from 0.6 to 1.2 mg/dL. Accordingly, the effects of ARBs on the animals in our experiments may not be unusual in humans. Moreover, we found that low-dose ARB treatment also significantly increased ¹⁸F-FDG activity in the blood without severely changing creatinine and BUN levels. This observation may further increase the probability of our finding that ¹⁸F-FDG activity increases in the blood of patients given ARBs.

Many patients who received ARB therapy show reversed renal function. In patients with renal problems, this is generally defined as the improvement of proteinuria or albuminuria (16). Reversed renal function, however, is commonly accompanied by an increased serum creatinine level. ARBs, particularly at high doses, decrease intraglomerular pressure, simultaneously improving proteinuria or albuminuria, which results in the renal protective effect (17). These patients commonly show an increased serum creatinine level, which is not considered a sign of renal insufficiency (18). The mechanisms underlying the decreased rate of urinary excretion of proteins and ¹⁸F-FDG are considered to be the same, that is, the decrease in intraglomerular pressure caused by ARB treatment.

The reversible reduction of ¹⁸F-FDG excretion by ARB may also suggest the utility of this agent for optimization of urinary ¹⁸F-FDG activity during PET imaging. Because an accumulation of ¹⁸F-FDG in the urine interferes with visualization of pelvic and abdominal abnormalities, radiologists or oncologists occasionally need to empty patients’ bladders before the PET scan (19) or even to retrograde-irrigate the urinary bladder with saline and a Foley catheter before or during PET data acquisition (20,21). To avoid such an invasive procedure, doctors also have used diuretics in an effort to reduce ¹⁸F-FDG activity in the urinary tract and reported improved diagnostic accuracy for ¹⁸F-FDG PET in abdominopelvic malignancies (12). Several experimental studies have also been performed to examine other agents for this purpose (22,23). The effective and reversible reduction of ¹⁸F-FDG excretion by telmisartan administration in the present study may indicate the usefulness of ARB for urinary ¹⁸F-FDG activity reduction, which may be helpful in the discrimination of pathologic from physiologic ¹⁸F-FDG uptake in abdominopelvic regions.

In the present study, a high-fat diet was used to make the status of the animal model close to that of patients who receive ARB. C57BK/6J mice on a regular research diet show a low serum low-density lipoprotein cholesterol level of about 20 mg/dL, which may create concerns about hypolipidemia in human beings (24). In contrast, in C57BK/6J mice fed a high-fat diet, the serum low-density lipoprotein cholesterol level elevates to about 75 mg/dL, which is closer to that of a human being (24). Body weight was lower in high-dose telmisartan-treated mice than in control mice on the same high-fat diet, probably because of the antiobesity effect of telmisartan (25).

As a limitation of the present study, we did not measure the ¹⁸F-FDG urinary excretion level, which may directly indicate whether the elimination of ¹⁸F-FDG is affected. We did, however, visually evaluate ¹⁸F-FDG excretion by autoradiography of kidney sections (Fig. 3). From these images, we made several observations. First, before ARB treatment, ¹⁸F-FDG markedly accumulated in the inner part of the medulla, which contains the loop of Henle and collecting duct. This finding indicates that, in the absence of ARBs, ¹⁸F-FDG is incompletely reabsorbed in proximal tubules and eliminated through the urinary system. Second, in the case of ARB treatment, the intensive accumulation of ¹⁸F-FDG in the inner part of the medulla markedly decreased to be as low as that in the renal cortex, which contains the renal corpuscles, proximal tubules, and distal tubules. This finding indicates the attenuated ¹⁸F-FDG excretion was caused by ARB treatment. Third, 3 wk after treatment cessation, the marked accumulation of ¹⁸F-FDG in the inner part of the medulla was reversed, and the accumulation pattern was similar to that before the ARB treatment. This finding suggests that the ¹⁸F-FDG excretion impaired by ARB treatment is reversible and that a short period of discontinuation may be a potential method to avoid this effect.

Taken together, our findings in this experimental study suggest that blockade of the renin angiotensin aldosterone system by ARB may affect the distribution of ¹⁸F-FDG by delaying its elimination. The increase in the background level of ¹⁸F-FDG, as well as the overestimation of SUV in target tissues, may adversely affect the accurate assessment of ¹⁸F-FDG PET images of ARB-treated patients. A brief treatment cessation may improve image quality. Nevertheless, there may be species differences between mice and humans, and our findings still need to be clinically confirmed.