REVIEW Annals of Nuclear Medicine Vol. 15, No. 3, 179-190, 2001 99mTc-MAG3: Review of pharmacokinetics, clinical application to renal diseases and quantification of renal function Kazuo ITOH Department of Radiology, JR Sapporo General Hospital About 14 years have passed since Fritzberg et al. developed 99mTc-MAG3 in 1986. The biological properties of this radiopharmaceutical are somewhat different from radioiodine labeled hippurate: it exhibits higher protein binding, slower blood clearance, higher extraction efficiency by tubular cells and larger excretion into the bile than the latter. Nonetheless, it has been widely used as the agent of choice for renal scintigraphy, diuresis renography, captopril augmented renography, and renal transplant. Renal scintigraphy with 99mTc-MAG3 can provide excellent image quality even in the presence of severely decreased renal function 99mTc-MAG3 is also used as an alternative to radio-hippurate for quantitative measurement of effective renal plasma flow. In this review, I focused on its pharmacokinetics, simplified quantitative methods and clinical application in renal diseases. Key words : 99mTc-MAG3, pharmacokinetics, renovascular hypertension, plasma sample method INTRODUCTION RADIONUCLIDE RENAL STUDY is the only method that provides information both on renal structure and function. The qualitative and quantitative information obtained from the study generally depends on the biological properties of the radiopharmaceuticals and sophisticated mathematical algorithms and empirical correlation studies. 99mTc-MAG3 (mercaptoacetylglycylglycylglycine) (Fig. 1) was introduced by Fritzberg et al.1 in 1986. The biological properties of 99mTc-MAG3 are somewhat different from those of radio-hippurate which has an excellent properties as effective renal plasma flow radioagent.1-24 However, it is now widely used as an alternative to radio-hippurate for the evaluation of nephrourological diseases such as renovascular hypertension25-40 and hydronephrosis,41-50 indirect cystography51 and renal transplant.52-60 In addition, a simplified method for the quantification of renal function, which has been reported by several investigators 61-78 is quite useful in routine Received March 26, 2001 . For reprint contact: Kazuo Itoh, M.D., Department of Radiology, JR Sapporo General Hospital, Higashi- l , Kita-3, Chuo-ku, Sapporo 060-033, JAPAN. E-mail: itohka51@ra2.so-net.ne.jp practice. However, the estimates attained by those simplified plasma-sample methods are not entirely in agreement.70,79,80 In this review, I focused on the pharmacokinetics, clinical application to renal disorders and quantitative algorithms, which will be helpful in routine clinical practice using 99mTc-MAG3. PHARMACOLOGICAL PROPERTIES Issues concerning the pharmacokinetic properties of 99mTc-MAG3 are summarized in Table I . Renal and plasma clearance, renal handling and urinary excretion ratios of 99mTc-MAG3 have been identified in animals in comparison with radioiodine labeled hippurate (OIH).1-7 The extraction efficiency for HPLC-purified 99mTc-MAG3 under constant infusion in rats was 85%, which is higher than 69% for OIH. I Probenecid and paraaminohippurate (PAH) inhibit renal clearance of 99mTc-MAG3 more than that of hippurate.1,3 PAH had no effect on iothalamate which is a glomerular filtration marker. These findings highly suggest that the largest fraction of 99mTc-MAG3 is excreted through the proximal tubular cells of the nephron. The recent study in pigs by Rehling et al.7 indicates that the total plasma clearance and renal clearance of 99mTc-MAG3 are about 75% that of OIH. The distribution of volume of 99m-Tc-MAG3 is 71 % that of iothalamate and 47% that of OIH. Protein binding is 90% for 99m-Tc-MAG3, 49% for OIH and 16% for iothalamate. RBC binding for 99m-Tc-MAG3 is (single injection/continuous injection) 1.0%/2.3%, which is significantly lower than l3.5%/9.0% for OIH and 3.1%/5.3% for iothalamate. The RBC binding is higher in the renal vein, which indicates incomplete back diffusion from RBC to plasma. It is more interesting and important that the renal plasma extraction of 99m-Tc-MAG3 is constant but significantly smaller after a single injection (0.54) than during continuous infusion (0.62). On the contrary, the renal plasma extraction of OIH decreases continuously from 0.85 to 0.52 at 3-1 50 min postinjection. They concluded that the phamacokinetic property of 99m-Tc-MAG3 of constant renal extraction is preferential to OIH as a tracer for renal function studies using a single injection technique. In human studies, pharmacokinetic properties of 99m-Tc-MAG3 have also been identified in comparison with OIH or 99m-Tc-DTPA.8-24) Plasma clearance ratio of 99m-Tc-MAG3/131-I-OIH is estimated to be 1.07-0.44. The volume of distribution of 99m-Tc-MAG3 is less than that of OIH. The protein binding for 99m-Tc-MAG3 is 75-90% and 53-74% for OIH. The urinary excretion per injected dose in healthy persons is about 70% by 30 min postinjection, which is almost equal to or less than that for 131-i-OIH. It is agreed that 99m-Tc-MAG3 gives an underestimated plasma clearance in comparison to OIH, but plasma clearance of both radioagents correlates very well (Table 2). Plasma clearance of 99m-Tc-MAG3 that is estimated by established methods is lower than that of OIH. These differences in pharmacokinetic properties between 99m-Tc-MAG3 and OIH in human beings are due to higher protein binding, lower distribution volume, and different tubular extraction efficiency of 99m-Tc-MAG3. Under the consideration of these pharmacokinetic differences of 99m-Tc-MAG3 and OIH, Bubeck et al. 11 chose the expression "Tubular Extraction Rate (TER)" as a new parameter analogous to "ERPF" for OIH and "GFR." They commented that TER might be used as a measure for the tubular function obtained with 99m-Tc-MAG3. Now, TER is used as a quantitative expression of function obtained by 99m-Tc-MAG3 renal study. However, most of clinicians is more familiar with ERPF as a renal function parameter than TER. When we convert TER to ERPF in routine practice, MAG3 clearance can be estimated from the equations in Table 1, or is simply divided by 0.53 to convert it to ERPF.76 99m-Tc-MAG3 is now easily prepared using commer-cially available kit. Difference in pharmacokinetics between kit-prepared and HPLC-purified 99m-Tc-MAG3 have been discussed in the previous papers 81-86 So, when we compare pharmacokinetics of 99m-Tc-MAG3_ with those of OIH and 99m-Tc-DTPA in animals and humans, we have to take the preparation of 99m-Tc-MAG3 into account. Kitprepared 99m-Tc-MAG3 tends to have a higher biliary excretion than HPLC-purified 99m-Tc-MAG3.85,86 CLINICAL APPLICATION TO RENAL DISEASES As compared to 131-I-OIH, the biological properties of 99m-Tc-MAG3 seem to be inferior, but the physical properties for external imaging is superior. In addition, clinical availability of an instant kit is better than 131-I-OIH. Image quality with 99m-Tc-MAG3 is higher than that with 99m-Tc-DTPA in the presence of decreased renal function.10,13 Therefore, renal study with 99m-Tc-MAG3 is considered the first choice in routine practice. Renovascular hypertension (RVH) Renal scintigraphy with an angiotensin converting enzyme inhibitor such as captopril is well known as captopril renography (CR) for the detection of renovascular hypertension. A renin-dependent kidney with unilateral, hemodynamically relevant renal artery stenosis (RAS) releases renin from the juxtaglomerular apparatus.25,26 Released renin promotes increased conversion of angiotensin I (AGI) to angiotensin II (AGII) in the lung. AGII in the circulation has a very strong pharmacological effect of peripheral artery contraction. As a result, systemic blood pressure is increased. These pathophysiological bases associated with renal ischemia are understood as renin-dependent RVH, Goldblatt's hypertension. AGII also contracts the efferent arteriole of the glomerulus rather than the afferent one. As a result, glomerular filtration is maintained as normal as possible. These pathophysiological phenomena are called "self-regulation" of the kidney. Glomerular filtration abruptly decreases after the administration of captopril which blocks conversion of AGI to AGII. Diagnostic criteria for 99mTc-MAG3 in RVH are not essentially different from those for 99mTc-DTPA.27 Captopril administration to a patient with RVH induces decreased renal clearance and prolonged renal transit.27,28,32-36 In consideration of the pathophysiological basis, CR with 99mTC-DTPA as glomerular filtration marker is theoretically preferable for detection of renal change to captopril in a renin-dependent kidney rather than 99mTc-MAG3 as the renal tubular radioagent. However, diagnostic accuracy with renal plasma flow markers such as OIH and 99mTc-MAG3 in RVH is not different from that with a glomerular filtration marker such as 99mTc-DTPA. Blaufox et al.34 evaluated diagnostic accuracy of CR in RVH with simultaneous 131I-OIH and 99mTC-DTPA administrations. There were no statistically significant differences in quantitative and qualitative accuracy, between OIH and DTPA or among quantitative parameters. The highest accuracy for quantitative CR was 56% with DTPA (n = 57) and 60% with OIH (n = 60), in both cases using the relative renal uptake parameter. Accuracy may be improved by supplement use of in vitro simulated plasma renin activity. In individuals with renal insufficiency (n = 17, GFR < 50 ml/min), small kidney (n = 17) and/or bilateral renal artery disease (n = 16), about 50% of CR are abnormal but nondiagnostic. In patients with GFR of 10 ml/min/1.73 m2 and/or split renal function of 10% or less, all quantitative and semiquantitative scintigraphic parameters were non-specific.30 False-positive results were found in less than 5%.34 As false positive causes, systemic hypotension during CR37 and calcium antagonists38 have been reported. The investigation of CR in RVH has focused on changes of renal function in the affected kidney, namely individual kidney function. It is identified by Muller-Suur et al.39 that global renal function assessed by 99mTc-MAG3 plasma clearance decreased in hypertensive patients with RAS but increased in patients without RAS. 99mTc-MAG3 clearance measurements during baseline and CR may not be informative for the detection of the affected kidney but can serve as additional diagnostic information on the presence of RVH in patients with hypertension. A new approach, aspirin renography, has been described by Imanishi et al.35 as possible to improve the diagnostic accuracy of captopril renography. The pathophysiological basis is that, in a patient with RAS, the synthesis of prostaglandin E2 (PGE2) is increased. The PGE2 itself formed in glomeruli, and leads to an increase in renal blood flow but no increase in the GFR. However, PGE2 as a vasodilator secondarily increases renin secretion and AGII production. As a result, it can have vasoconstrictive effects on the kidney. Administration of aspirin to a patient with RVH Ieads to inhibition of PGE2 synthesis and reduces stimulation of the renin angiotensin system. In pathophysiological cascade of renal ischemia associated with RAS, aspirin plays a notable role similar to captopril. The method is theoretically very attractive. They concluded that aspirin renography was more accurate for the detection of RVH than CR. In a comparative study40 between aspirin renography and captopril renography in 75 patients with hypertension, the sensitivities for unilateral RAS or bilateral RAS (i.e., stenosis that was at least unilateral) were, respectively 88% and 88% for captopril renography and 82% and 94% o or asprrm renography (ns). The overall specificity was 75% for captopril and 83% for aspirin renography (ns). It was concluded that for the identification of RAS, the usefulness of aspirin renography equals, but does not surpass, that of captopril renography. Combined administrations of aspirin and captopril may be expected to be more effective than single administration of each drug.31 However, the combination study with aspirin and captopril may need further investigation in the future before it is accepted as a clinical application in RVH. Diagnostic limitations of CR for identification of RVH have been disclosed even though the method is theoretically superior. It should be kept in mind that CR is utilized to identify the presence of AG II-dependent renal dysfunction but is also a good indicator to predict blood pressure response to revisualization. The positive predictive value of positive CR is 100(~o, while the negative predictive value of negative CR is 85%.33 Hydronephrosis and Cystography Diuresis renography (DR) is utilized to differentiate true obstruction (obstructed hydronephrosis) from a dilated non-obstructed system (stasis) by imaging after intravenous administration of furosemide. Diagnostic criteria43,47 used for DR have been established from clinical data mainly based on 99mTc-DTPA. Urinary excretion of 99mTc-MAG3 is higher than 99mTc-DTPA. Therefore, 99mTc-MAG3 is considered to be preferable for the evaluation of urinary drainage to 99mTc-DTPA. Furosemide response was similar in both radioagents. 10,45,50 Diagnostic accuracy depends on the load of diuretic before and during the study, preserved renal function and time of furosemide injection.41,48 In general, DR is considered to be higher in sensitivity than specificity, namely fewer false negative results and more false positive results. As a new modification, gravity-assisted drainage (GAD) was introduced by Wong et al.50 This method can be helpful to differentiate between obstruction and non-obstruction in renal units with diuretic Tl/2 > 10 min in a standard DR. The method and diagnostic criteria are illustrated in Figure 2. Using GAD > 50% in 62 renal units with Tl/2 > 20 min in the standard DR, the sensitivity was 89.4%, the specificity was 83.9%, and the accuracy was 73.7%. Using GAD > 50% in 52 renal units with Tl/2 = 10-20 min, the sensitivity was 100%, the specificity was 79.5%, and the accuracy was 82.7%. There was only one case of obstruction in 131 renal units with Tl/2 < 10 min. Indirect radionuclide cystography (IRC) with 99mTc-MAG3 is advocated as a favorable method rather than direct or indirect cystography with 99mTC-DTPA in children, because of its high extraction rate and non-invasiveness.51 However 99mTc-MAG3 IRC missed two-thirds of refluxing kidneys. Using 99mTC-DMSA scintigraphy as reference, micturition cystoureterography detected 91 % of the patients with DMSA abnormalities of at least one kidney, direct radionuclide cystography detected 95%, and IRC detected 46% and 43%, respectively, in groups of reflux grades I and II Therefore, 99mTc-MAG3 IRC reflux cannot be utilized as the sole technique for the detection of vesicoureteric reflux. Renal transplant The assessment of function of a transplanted kidney is one of the major issues in radionuclide renal study. The medical complications after renal transplantation include surgical problems after anastomoses of vessels and ureter, rejection (superacute, accelerated, acute and chronic), cyclosporin toxicity to the kidney and acute tubular necrosis (ATN) which is commonly seen in the immediate posttransplantation period in cadaveric kidneys 52 99m-Tc-MAG3, 99m-Tc-DTPA and 131-I-OIH are all acceptable. Because of higher extraction efficiency, 99m-Tc-MAG3 is preferred over 99m-Tc-DTPA,53 especially in patients with decreased renal function 54,60 There have been many indices of renal perfusion, renal function and transit time, which are utilized in the evaluation of medical complications.60 Although medical complications such as acute rejection, ATN, chronic rejection and cyclosporin nephrotoxicity cannot entirely be differentiated from each other, a simple flow chart on differential diagnosis of medical complications after renal transplantation is summarized by Dubovsky et al.60 Quantitated renal function and transit time are considered as important indices for differentiation of complications in the transplanted kidney. As a method of tracer transit index, Li et al.55 proposed C20/3 in the renogram, which should be recommended for the differentiation of acute rejection from ATN, because of its technical simplicity and high diagnostic accuracy. Renal failure In acute renal failure, the radionuclide study is not only important for the diagnosis and the evaluation of preserved renal function, but is also needed to access the potential of functional recovery or prognosis of the failed kidneys. In addition, it is often asked on the basis of the radionuclide renal study, whether the unilateral kidney with severely damaged function should be kept or removed in the operation 99m-Tc-MAG3 is also useful in the evaluation of viability and prognosis in acute renal failure in renal transplantation 57 Cortical uptake phase (CUP) image, which is a 2-min image acquired I min after 99m-Tc-MAG3 administration, is visually analyzed according to standardized semiquantitative guidelines. Interpretation is expressed in tubular injury severity score (TISS) that ranges from I (a normally functioning renal transplant) to 6 (a photogenic defect in place of renal transplant). All five patients with TISS of 5 and 6 lost the transplant. Only 1 of 10 patients with TISS of 4 lost the transplant. All patients (n = 49) with TISS of less than 4 recovered renal transplant function. They suggest that CUP image of 99m-Tc-MAG3 is an accurate prognosticator in patients with early postoperative renal transplantation dysfunction. It is easy to understand that blood supply plays a critical role in the functional maintenance and recovery of the organ, of course the failed kidney. No and poor blood supply, namely no and poor early uptake of 99mTc-MAG3, indicates very low potential of functional recovery of the kidney. In this context, the early parenchimal uptake of 99mTc-MAG3 in the kidney may serve as an indicator of functional severity as well as functional recovery. The method must be applicable to acute renal failure due to any cause and also surgical manipulation of the kidney with very poor function (Fig. 3). In addition, the semiquantitative parameters such as TISS should be altered to quantitative parameters such as kidney to background ratio, early renal uptake or TER. Clinical implementation of the methodology should be investigated in the future. Quantitation of renal function One of the major goals in radionuclide renal study is an appropriate evaluation of renal function in many diseases which may induce renal dysfunction. In that context, quantitative determination of renal function using renal radioagents is essential and important in radionuclide renal study. Radionuclide study using glomerular filtration markers is proved to be simple and most accurate in routine practice.72 There have been several methods to quantify renal function following a single injection (Table 3 ). The steady-state infusion method is most accurate for the determination of renal clearance. However, this method is technically complicated and is only performed in research study. The 2-compartment method after single injection is also proved to be accurate and is technically easier than the steady-state infusion method. Most clinical studies on the determination of plasma clearance employ this method. The I -compartment method is practically easier than the 2-compartment method. In the determination of GFR with 99mTc-DTPA, the l-compartment method with 2 samples is more accurate than the simplified single-sample method and is indicated to a patient with severely decreased GFR less than 20-30 ml/min in clinical practice.72 However, there is only one investigation that shows the relationship between 2-compartment and 1-compartment methods for the determination of 99mTc-MAG3 plasma clearance 61 Therefore, the 1-compartment method is considered not to play an important role in quantitative study using 99mTc-MAG3 in routine practice. The external counting methods by gamma camera67,71,73-75,77,78 are very simple and give a simultaneous evaluation of renal function. These methods are useful in the evaluation of an individual kidney function and the determination of global kidney function in infants and children in whom blood drawing is often difficult. However, it is important to remember that not all children may have received an adequate percentage dose to constitute a reliably diagnostic study during the interpretation of the findings in pediatric radioisotope studies 65 In addition, the gamma camera methods are considered to be inaccu-rate in the determination of global kidney function 72,78 All equations used in the gamma-camera uptake method are determined with a correlative study of plasma sample methods as reference. As long as the count-based gamma-camera method is based as reference for the plasma sample method for the determination of global renal function, it cannot overcome the accuracy of reference method. Now, simplified single-sample methods are recom-mended for the determination of TER with 99m-Tc-MAG3 .72 There have been 3 representative algorithms as single- sample method with 99m-Tc-MAG3 (Table 4). Bubeck's method 62.64 is utilized for adults and children. Russell's method 60,69 is also applicable to both. Piepsz's method 63 is dedicated to children. In comparison to Bubeck's and Russell's methods, Bubeck' s method gives a significantly lower TER than Russell's method,70,79,80 particularly in range of TER higher than 200 ml/min/1.73 m2 (Fig. 4). I used to report that Bubeck's algorithm may be better than Russell's, because the former employed the steady-state infusion as reference 79 On the contrary, the latter employed the 2-compartment method after single-injection as reference. Recently, it is reported that Russell's method may be better than Bubeck's. 80 It will become clear through further investigation which of the methods is preferable in routine practice. It will be also clarified whether accuracy and reliability of simplified single-sample method with 99m-Tc-MAG3 may depend on a level of preserved renal function, TER. Nonetheless, all simplified single-sample methods proposed until now are still recommended as the first choice for the determination of TER in both kidneys. ADMINISTERED DOSE AND RADIATION DOSE For adults, a relatively large range of activity is adminis-tered: 70-1 85 MBq for 99m-Tc-MAG3 , 70-200 MBq for 99m-Tc-DTPA.78 For dose adaptation in children, body surface correction should be used and the minimum in children is recommended to be 1 5 MBq for 99mTc-MAG3 and 20 MBq for 99mTc-DTPA. The radiation dose of 99mTc-MAG3 is summarized in Table 5.87 Rapid bladder voiding is essential to decrease the radiation dose to the patient. An effective dose with 37 MBq (1 mCi) of 99mTc-MAG3 and 99mTC-DTPA gives less radiation than a plain abdominal radiograph in adults (1 .4 mSv, 0.05 mSv for 88-90 plain chest radiograph). CONCLUSION The radionuclide renal study is only one method to supply renal structure, urodynamics in urinary collecting system and renal function in one test. In Japan, it was performed as one of the major examinations in routine nuclear medicine but is decreasing in number now. I wonder where it is,going in the new century in Japan. Woolfson et al.91 descnbed that "much of the progress in renal nuclear medicine has been driven by technological development, but without rigorous assessment the value of some of these studies has been overestimated. The only tests to achieve gold standard status are the isotopic GFR, the DMSA renogram to detect cortical abnormalities and the captopril renogram when used to define those hypertensive patients who will not benefit from renovascular intervention. Consensus guidelines must be followed and routine protocols for combination tests must be developed, but even so isotopic renography is likely to be overtaken by competing technologies which can provide one test to give simultaneous information about both structure and function." Their comments may be true, but I do not think that the clinical utilization of radionuclide renal study has reached the maximum state in Japan. A concept of TER obtained by 99mTc-MAG3 study is not familiar to most clinicians. Russell and Dubovsky of the University of Alabama at Bermingam68 describe that such problems have been resolved by education of students, residents and physicians in the institution. In order to maintain such circumstances in Japan, we have to learn from their many achievements so far, that we should try to always give quantitative estimates in routine study, which is accurate, reliable and universally applicable. of course, a new radiopharmaceutlcal is very important in the progress of renal nuclear medicine.92 I would like to close this paper with comments by Levey,93 that "estimation of GFR from renal clearance of radioisotope-labeled filtration markers, using a bolus infusion and spontaneous bladder emptying, is accurate, precise, and more convenient than the classical inulin clearance technique, and that measurements of GFR should be included both in clinical practice and in clinical research." His comments must be also suited to TER using 99mTc-MAG3 at present and in future (Table 6).94 ACKNOWLEDGMENTS I would like to express my sincere thanks to M. Satoh and E. 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