Single-Shot Cardiorenal Scintigraphy with ^99mTc-Tetrofosmin: A Dynamic Characterization at Rest and During Adenosine Infusion

MATERIALS AND METHODS

We studied 30 consecutive patients (14 men, 16 women; mean age ± SD, 62 ± 14 y) scheduled to undergo myocardial gated SPECT to investigate myocardial ischemia or viability; coronary angiograms were available for 18 patients, and 11 of them showed coronary artery disease. Twenty-four patients were hypertensive (7 with verified renovascular disease), and 7 were diabetic; 6 patients had dilated cardiomyopathy. Vital statistics and main clinical parameters are reported in Table 1.

A standard dual-day scintigraphic protocol was applied for the 21 patients who underwent the stress test; adenosine was administered on the first day, without significant symptoms except for transient dyspnea in 1 patient.

The patients also gave their informed consent for a renal acquisition during the rest study (30 patients) and during adenosine infusion (21 patients) and to undergo an additional standard renal study with the glomerular tracer ^99mTc-diethylenetriaminepentaacetic acid (DTPA) (74 MBq) after 1 wk (24 patients). Figure 1 outlines the main steps of the cardiorenal scintigraphic protocol.

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FIGURE 1. 

Flow chart of scintigraphic cardiorenal acquisition protocol. G-SPECT = gated SPECT.

Although not strictly required by the study design, laboratory data and sitting blood pressure values (Vital Signs Monitor; Welch Allyn) (30 patients) were retrieved with patient consent from clinical records, along with cardiac, carotid, and renal Doppler ultrasound data, which were available in 29, 20, and 19 patients, respectively, as shown in Table 1.

RESULTS

Renal ^99mTc-Tetrofosmin Scintigraphy

^99mTc-Tetrofosmin and ^99mTc-DTPA

Compared with ^99mTc-DTPA, ^99mTc-tetrofosmin permitted better definition of kidney images and renographic curves because of a higher kidney-to-background activity ratio (Fig. 2); bilaterally or unilaterally decreased renal uptake was appreciable, as illustrated in Figure 3. In 10 patients, the amplitude of the late excretory phase of the right-kidney renogram obtained with ^99mTc-tetrofosmin was increased by a superimposed biliary activity.

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FIGURE 2. 

Examples of kidney images (over uptake interval) and renographic curves obtained with ^99mTc-tetrofosmin (A), in comparison with ^99mTc-DTPA (B), in patient with normal renal function.

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FIGURE 3. 

Renographic curves and kidney images obtained with ^99mTc-tetrofosmin in patient with moderate reduction in renal function (creatinine clearance, 56 mL/min) (A) and patient with right renal artery stenosis (B). Continuous line = right kidney; dotted line = left kidney.

At quantitative analysis, ^99mTc-tetrofosmin had a significantly higher renal uptake index than did ^99mTc-DTPA, whereas no significant differences between the 2 tracers were observed for right- and left-kidney separate percentage uptake and for times to peak activities (Table 2).

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TABLE 2

Main Scintigraphic Parameters Compared Between Tetrofosmin and ^99mTc-DTPA by Paired Student t Test

Close correlations were found between ^99mTc-tetrofosmin and ^99mTc-DTPA for uptake index (r = 0.77, P < 0.001) and separate kidney percentage uptake (r = 0.96, P < 0.001), with no appreciable differences in right-kidney versus left-kidney behavior (Fig. 4A). ^99mTc-tetrofosmin and ^99mTc-DTPA time to peak activities were weakly correlated, with no clear differences in right versus left kidney (Fig. 5).

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FIGURE 4. 

Representative correlations of ^99mTc-tetrofosmin uptake with ^99mTc-DTPA uptake (A) and renal functional parameters (B). • = right kidney; ▴ = left kidney; RI = Doppler ultrasound renal resistance index; s.k. = single kidney; SKU % = separate kidney uptake (percentage total-kidney uptake). Uptake index (UI) is in percentage injected dose.

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FIGURE 5. 

Correlation between time to peak (TP) for ^99mTc-DTPA and ^99mTc-tetrofosmin in right and left kidneys. • = right kidney; ▴ = left kidney.

^99mTc-Tetrofosmin and Renovascular Disease

In the 7 patients with angiographically proven significant renal artery stenosis, the baseline uptake index was lower in the stenotic kidney (3.67 ± 1.9 vs. 5.70 ± 2.46, P < 0.05) (Fig. 3). Because of scanty renal angiographic data in the control population (n = 3), the ^99mTc-tetrofosmin uptake index was compared between renovascular and nonrenovascular patients on the basis of their renal Doppler ultrasound data. A significantly lower uptake index was observed in the affected kidneys of renovascular patients than in individuals without renal artery stenosis, considered as the average uptake of the 2 kidneys (3.29 ± 1.76 vs. 7.16 ± 2.36, P < 0.01).

Renal Scintigraphy and Gated SPECT

Comparing the group of patients with normal myocardial perfusion patterns (10 patients) and those with baseline or stress perfusion abnormalities (15 patients), we found that the resting renal uptake index was significantly lower (12.52 ± 3.98 vs. 16.09 ± 4.02; P < 0.05) in the patients with abnormal perfusion.

Comparison with Other Clinical Data

As shown in Table 3, subdividing the patients into 2 groups—those above and those below the median values of different renal and cardiovascular parameters—showed the ^99mTc-tetrofosmin uptake index to be lower in those who were more compromised.

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TABLE 3

Tetrofosmin Uptake Index in Different Parameters Subdivided According to Median Values

The ^99mTc-tetrofosmin uptake index was strongly related to serum creatinine and the Doppler index of renal vascular resistances (Fig. 4B). In addition, significant correlations were found with age (r = −0.76, P < 0.005), log₁₀ brain natriuretic peptide N-terminal levels (r = −0.65, P < 0.005), and myocardial and carotid intima-media wall thickness (both, r = −0.61, P < 0.005).

Effect of Adenosine

Adenosine caused a significant decrease in renal ^99mTc-tetrofosmin uptake index (from 14.12% ± 4.50% to 11.81% ± 3.33%, P < 0.005). A more pronounced decrement was observed in the 10 subjects with a baseline uptake index greater than 13.37% (median value) than in those who were below the median (n = 11) (−3.72 ± 2.66 vs. 0.75 ± 3, P < 0.005). Accordingly, a negative correlation was found between resting ^99mTc-tetrofosmin uptake index and its changes after adenosine (r = −0.56, P < 0.005).

Patients with a positive adenosine test for myocardial perfusion abnormalities (n = 10) had a lower renal ^99mTc-tetrofosmin uptake index at baseline than did those with a negative test (n = 11) (11.6 ± 4.5 vs. 15.23 ± 4.15, P < 0.05) and a lesser decrease in renal uptake index after adenosine (−0.92 ± 3.49 vs. −3.57 ± 2.32, P < 0.05). Of the 7 patients with renal artery stenosis, the adenosine test was performed in only 4, and no statistical analysis was performed. However, in 3 patients adenosine induced a ^99mTc-tetrofosmin uptake index decrement that was clearly more pronounced on the affected side, with an increase in kidney-to-kidney asymmetry as shown in Figure 6.

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FIGURE 6. 

Adenosine effect in patient with bilateral renal artery stenosis more severe on right side, detected by ^99mTc-tetrofosmin (uptake interval).

DISCUSSION

It has been known for a long time that heart and kidney are related in cardiovascular pathophysiology. Recent studies have focused on this relationship as a link to cardiovascular risk and prognosis (1–8), and the term cardiorenal syndrome is increasingly used to define a condition of reciprocal dysfunction of the heart and kidney, with different clinical presentations depending on which organ is primarily involved (1).

The assessment of kidney function in clinical practice usually relies on estimation of the glomerular filtration rate by standard laboratory parameters such as serum creatinine or creatinine clearance; however, renal perfusion abnormalities may precede glomerular filtration changes because of the regulation of filtration pressure and may be more relevant in the early assessment of cardiorenal pathology and prognosis (20). Furthermore, clinicians often need the estimation of separate kidney function, which is noninvasively obtainable only by scintigraphic examination.

Gated SPECT with ^99mTc-tetrofosmin is widely used for the study of cardiac perfusion and function and can also detect silent ischemia (9,10). The present study indicated that this tracer may also allow functional imaging of the kidneys, suggesting the application of the combined technique to the evaluation of cardiorenal disease.

We found a proportionality between ^99mTc-DTPA and ^99mTc-tetrofosmin renal uptake index, but the kidneys appeared to extract a greater proportion of ^99mTc-tetrofosmin than of ^99mTc-DTPA, with better images and renographic curves. Hepatobiliary extraction of the tracer may have disturbed the appearance of the late right-kidney image and renographic curve and explain the greater (though not significantly so) delay in average time to peak in the right kidney, as reported in Table 2, but did not appear to affect renal counting rate in the interval of functional evaluation. Taking into account the observation by Higley (12) of an approximately equal uptake of ^99mTc-tetrofosmin by the kidney and liver, and the ^99mTc-tetrofosmin and ^99mTc-DTPA uptake index that we found, we could hypothesize for tetrofosmin a renal clearance far greater than glomerular filtration rate, suggesting a prevailing tubular extraction as for blood flow renal tracers. It may be interesting to observe that mean ^99mTc-tetrofosmin renal uptake index (13%) was comparable to observations reported by Higley et al., who found a 10% fractional urinary elimination of the radioactive dose at 2 min after injection in rats and at 5 min in healthy human volunteers (12). The biodistribution study by Higley et al. (12) showed an approximately equal contribution of the kidney and liver to the elimination of the injected dose. Taking these data and our uptake index results into account, ^99mTc-tetrofosmin uptake index was also proportional to renal function estimated by serum creatinine in the explored range and could also be associated with several other indicators of severity of cardiovascular disease. These findings suggest that cardiorenal scintigraphy may be useful in a wide range of clinical conditions requiring a combined evaluation of heart and kidney, such as arterial hypertension, diabetes, chronic heart or renal failure, and heart or renal transplantations (1–8,21). In addition, it may contribute valuable information to the diagnosis and functional evaluation of renovascular forms that are frequently associated with cardiovascular disease (22). Patients referred for coronarography represent an important group in which renal evaluation may distinguish healthy individuals from those at risk for the development of acute radiocontrast-induced nephropathy (23). A noninvasive study of both myocardial perfusion and renal function is also required in the preoperative assessment of patients with thoracoabdominal aortic aneurysm and peripheral vasculopathy (24,25).

The decrease in renal ^99mtc-tetrofosmin uptake index after adenosine appears to agree with the statement that sustained vasoconstriction is the first response to purinergic stimulus in the kidney, where adenosine is a main effector of the tubuloglomerular feedback mechanism regulating preglomerular resistance (26,27). This effect seemed to be less pronounced in the more seriously affected kidneys, possibly suggesting a decreased vasoconstrictive purinergic renal reserve that can be scintigraphically detected. A substantial decrease in renal ^99mTc-tetrofosmin uptake was also observed in healthy volunteers during exercise stress (12), and it is interesting that adenosine has been suggested as a mediator of the so-called muscle metabolic reflex induced by exercise on the heart and kidneys via sympathetic stimulation, eliciting both an increase in cardiac output and a decrease in renal perfusion and function (28,29). The fact that renal response to adenosine was reduced in the presence of myocardial perfusion abnormalities could be tentatively interpreted as being due to impaired renal purinergic reserve concomitant with the alterations in coronary reserve.

A more pronounced response to adenosine in the affected kidneys of some renovascular patients could theoretically be explained by the offset of an active vasodilatory reserve downstream from the arterial stenosis.

Finally, the effect of adenosine on renal ^99mTc-tetrofosmin uptake could be due to a nonspecific decrease in renal perfusion pressure in cases in which a significant peripheral vasodilation and blood pressure drop may follow drug administration.

The study had some limitations. ^99mTc-tetrofosmin has comparable renographic characteristics to ^99mTc-DTPA but a greater uptake rate, suggesting a greater clearance rate. However, urinary renal clearance was not measured in our study, to avoid adding a cumbersome procedure to routine diagnostic testing for outpatients. Moreover, hepatobiliary excretion of ^99mTc-tetrofosmin might theoretically interfere with renal functional imaging, especially of the right kidney and in the presence of overt renal insufficiency.

Although the low protein binding combined with the highly lipophilic and diffusable structure of ^99mTc-tetrofosmin suggests that perfusion rate is a major determinant of renal uptake, to our knowledge the renal clearance pathways of ^99mTc-tetrofosmin have not yet been investigated, and dedicated studies are needed to clarify these aspects. The results of our study imply an association between ^99mTc-tetrofosmin renal uptake and several indices of cardiorenal severity. However, a statistical analysis by multiple comparisons was not attempted because of the limited number of patients, and consequently the weight of each functional parameter could not be assessed. Finally, a definite interpretation of the renal effects of adenosine is not possible because of the limited number of observations and the heterogeneity of the patient series. Therefore, obtaining a postadenosine renal scan remains questionable at the moment, unless dedicated studies address its clinical significance.

CONCLUSION

The kidneys can be evaluated by a simple scintigraphic protocol during ^99mTc-tetrofosmin gated SPECT in a single-shot dual study without prolonging the procedure or adding further radioactive burden. One can shorten the dual study by performing a 15-min renal acquisition during a gated SPECT fast imaging protocol (15). Cardiorenal scintigraphy with ^99mTc-tetrofosmin may thus be proposed especially in those patients undergoing gated SPECT in whom a significant risk of overt or subclinical renal disease exists. Adding renal functional imaging to the cardiac study could permit the detection of kidney abnormalities consistent with vascular, parenchymal, or obstructive kidney disease.

Moreover, our results indicate that renal ^99mTc-tetrofosmin uptake is a functional parameter linked to many indices of cardiorenal severity. Such uptake may be of prognostic significance in the identification of patients subject to radiocontrast-induced nephropathy and heart failure patients in whom decreased renal function adds a strong negative marker.

Although the first conclusion leads to an easy and useful nuclear medicine application that could be planned immediately for selected patients when cardiorenal disease is suspected, the second conclusion suggests a need for dedicated validation studies to assess pathophysiologic and prognostic significance in specific cardiovascular and renal conditions.