Comparison of different radioactive agents for the detection of renovascular hypertension with captopril in a rat model.

In Goldblatt hypertension in rats produced by implanting a silver clip on the left renal artery, captopril induces a greater difference in the 1-min uptake of diethylenetriaminepentaacetic acid (DTPA) between the two kidneys than in baseline uptakes, similar to the experiences in unilateral renovascular hypertension in man. The combination of captopril and furosemide induces an even greater difference in renal uptakes than with captopril alone in this rat model. In paired experiments, DTPA complexes were used as a standard to compare the differences in renal uptake between the two kidneys after captopril-furosemide with other existing and potential renal radiodiagnostic agents. No statistically significant difference was found between DTPA, glucoheptonate, dimercaptosuccinic acid, aminated dextran, or lysozyme. However, the differences in renal uptake were significantly less with hippuran than with DTPA. Furosemide and captopril caused delayed renal retention of hippuran after one minute. This response appeared to be due to non-specific volume depletion because it occurred in both clipped and unclipped kidneys.

Evaluation of cyclosporine nephrotoxicity in rats with various renal radioactive agents.

The efficacy of different radiodiagnostic agents for demonstrating the decline in renal function from cyclosporine (CyA) nephrotoxicity was assessed in rats receiving a standard dose of the drug for 2 wk, compared with control rats. The agents included [99mTc]DTPA, [131I]hippuran, [111In]lysozyme, [99mTc]glucoheptonate (GHA), [99mTc]dimercaptosuccinate (DMS) and [111In]aminated dextran (amdex). A small dose of [99mTc]- or [111In]DTPA was administered simultaneously to normalize the results for variations in drug response from one animal to another. There were statistically significant differences in the detectability of the renal functional impairment by plasma clearance, early and 2-hr renal uptake among the different agents. However, none was clearly superior to DTPA. This conclusion is consistent with previous studies which showed a parallel decline in glomerular filtration rate (GFR) and effective renal plasma flow in acute CyA toxicity probably due primarily to vasoconstriction.

Detection of diffuse glomerular lesions in rats: I. Comparisons of conventional radioactive agents.

Conventional renal diagnostic agents, [131I]hippuran, [99mTc]glucoheptonate (GHA), and [99mTc] dimercaptosuccinate (DMS) were compared with [99mTc] or [111In] diethylenetriaminepentaacetic (DTPA) for the detection of glomerular damage in rats compared with controls. The glomerular lesions were induced by the i.v. injection of puromycin aminonucleoside (PA) 9 days before the radionuclide studies, a model of spontaneous "minimal change" glomerulonephritis in humans. Computer-generated early renal uptake of [99mTc]DTPA or GHA correlated with the glomerular filtration rate (GFR) quantitated by biexponential plasma clearance of DTPA administered by single i.v. injection. The early renal uptake of hippuran and DMS correlated poorly with GFR as assessed by DTPA clearance. However, the 2-hr renal retention of DMS correlated well with the DTPA clearance. None of the parameters measured with [131I]hippuran correlated well with DTPA clearance, probably because of decreased protein plasma binding of hippuran secondary to hypoproteinemia in this experimental model. It was concluded that none of these agents was superior to labeled DTPA for the detection of glomerular damage in this experimental model.

Comparison of different radioactive renal agents in cisplatin-induced tubular toxicity in rats.

The efficacy of five different radiodiagnostic agents for detecting renal tubular dysfunction induced with cisplatin in rats was compared to controls. Diethylenetriaminepentaacetic acid (DTPA) labeled with 99mTc or 111In was administered simultaneously with each of the other four agents [99mTc]glucoheptonate, [99mTc]dimercaptosuccinic acid, [131I]hippuran and [111In]lysozyme) as a standard to normalize for differences in functional impairment from animal to animal from the same dose of cisplatin. The 2-hr plasma clearance and computer-generated 2- to 3-min uptake in the two kidneys with [99mTc]dimercaptosuccinic acid were significantly inferior to similar measurements with the other agents in differentiating abnormal from normal function. The 2-hr uptake of [99mTc]glucoheptonate and [111In]lysozyme proved of no value in this differentiation. The late renal retention of [99mTc]dimercaptosuccinic acid well separated the cisplatin from control rats, but the greatest difference was observed by the 2-hr uptakes of [131I]hippuran and DTPA.

Enalaprilat-enhanced renography in a rat model of renovascular hypertension.

The effect of rapid converting enzyme inhibition (CEI) with intravenous enalaprilat on technetium-99m-(99mTc) diethylenetriaminepentaacetic acid (DTPA) and 99mTc-dimercaptosuccinic acid (DMSA) renograms was evaluated in rats with two-kidney, one-clip renovascular hypertension. Rapid sequential DTPA renograms, performed immediately before and five minutes after enalaprilat injection (30 micrograms/kg), demonstrated a selective decrease in clipped kidney DTPA plasma clearance following CEI and no significant effect on unclipped kidney function. Pre- and post-CEI data were obtained with a single injection of DMSA by administering enalaprilat five minutes after the radiopharmaceutical. Enalaprilat slowed the rate of DMSA accumulation in clipped relative to unclipped kidneys, and reduced the clipped/unclipped kidney ratio of absolute DMSA uptake at 10 and 30 min. DTPA and DMSA were equally effective in demonstrating the CEI effect. Enalaprilat was also compared with captopril (3 mg/kg, intraperitoneally), using sequential DTPA renograms. Clipped kidney DTPA plasma clearance was reduced to an identical degree (40%) by both converting enzyme inhibitors. Clinical renographic protocols can probably be devised to take advantage of the rapid, reliable CEI of enalaprilat, thereby shortening total procedure time.

Labeling of platelets with oxine complexes of Tc-99m and In-111. Part 1. In vitro studies and survival in the rabbit.

We have used both Tc-99m oxine and In-111 oxine to study the effects in the rabbit of various parameters on platelet labeling and the in vivo survival of platelets harvested by four different methods. For In-111 oxine, platelet labeling in saline produces much higher efficiencies (90%) than labeling in the presence of plasma (20%), with no significant shortening of in vivo survival (1% survival at 5.9 days). For Tc-99m oxine, labeling efficiencies are considerably lower (30%) and survival is shorter (1% survival at 3.8 days). For both radioagents, a 30-min labeling incubation at room temperature is suggested.

Platelets labeled with oxine complexes of Tc-99m and In-111. Part 2. Localization of experimentally induced vascular lesions.

Using rabbit platelets harvested and labeled with either Tc-99m or In-111 oxine as described in Part 1, we have successfully imaged experimentally induced fresh venous thrombi and newly injured arterial intima. Visualization of lesions up to 6 hr old is striking. Thrombi and arterial damage 24 hr old, however, were usually not imaged successfully; nor were preformed platelet-poor arterial emboli. The varying rates of platelet deposition in vascular lesions of different ages and types account for these observations. Should human cells prove as effective, widespread clinical application is anticipated.

Comparison of renal extraction efficiencies for radioactive agents in the normal dog.

The renal extraction efficiencies for various radioactive agents were measured in normal anesthetized dogs during 1 hr after a single intravenous injection. Radioassays were made on serial blood samples drawn simultaneously from the aorta upstream from the renal arteries and from one renal vein. As a reference substance [131I]o-iodohippurate was injected concurrently in all experiments. Blood clearances from serial venous samples and urinary excretion also were measured. Extraction efficiency from whole blood was calculated as (A-V) divided by A, where A = aortic concentration and V = renal venous concentration. This ratio for commercial [131I]o-iodohippurate fell steadily from 88% at 30 sec to 50% at 1 hr. For "purified" [131I]o-iodohippurate the fall was less marked, to 61% at 1 hr. The EE ratios for all other agents were stable after the first minute. The Tc-99m complexes of DTPA, glucoheptonate, and acetylcysteine had ratios averaging 27-29%. The ratios of Tc-99m DMS and Hg-197 chlormerodrin had much lower average values of 8 and 14%, respectively. None of the newer agents approached the extraction efficiency of [131I]o-iodohippurate.

Technetium-99m DADS complexes as renal function and imaging agents: II. Biological comparison with iodine-131 hippuran.

To find a 99mTc agent with a high renal extraction efficiency similar to [131]hippuran, 21 analogs of DADS were labeled and evaluated. Preliminary screening by serial gamma camera imaging in rabbits showed that most analogs had a higher liver uptake and/or slower renal clearance, than hippuran. Three agents (P-DADS, AP-DADS, and CAP-DADS), exhibiting a relatively rapid blood clearance and lower liver uptake in the rabbit, were studied in greater detail in comparison with hippuran and CO2-DADS-A, the best analog to date. In the rat, the plasma clearance of the four DADS analogs was slower than that of hippuran. In rats with tubular damage induced by cisplatin, the difference in renal retention at 1 hr compared to controls was much greater with hippuran than with the DADS compounds. In the dog, there was marked hepatic retention of the four DADS compounds. In volunteers, serial posterior images obtained with these [99mTc]DADS complexes showed significant hepatic as well as renal activity. The 1-hr plasma clearance and urinary excretion were much lower than with simultaneously injected hippuran. Although these 99mTc agents are satisfactory for imaging the kidneys, they closely mimic the biodistribution of hippuran only in the rabbit, and not in the rat, dog, or man.

Detection of diffuse glomerular lesions in rats: II. Comparison of indium-111 cationic small macromolecules with technetium-99m DTPA.

Dextrans with average molecular weights of 5,000, 10,000, and 17,500 and inulin were rendered cationic by amination with 2-bromoethylamine hydrobromide. After limited coupling with DTPA cyclic dianhydride, they were labeled with 111In. A good correlation was found between their early renal uptake quantitated by camera-computer techniques and their renal clearance from multiple plasma samples in rats with glomerular damage induced by puromycin aminonucleoside and controls. However, there was poor correlation between the early renal uptake of these agents and the clearance of simultaneously injected [99mTc]DTPA. The 2-hr organ distribution and urinary excretion of these agents were compared with the corresponding values of DTPA. The differences in clearance between rats with glomerular damage and controls were greater with aminated dextran (mol wt 5,000) than with DTPA, confirming previous work with infusions of nonradioactive charged dextrans and neutral inulin. The cationic dextrans appear to reflect the presence or absence of the normal anionic charge of the glomerular membrane as well as changes in filtration rate. Aminated inulin did not differentiate between controls and rats with glomerular disease any better than DTPA, probably because the number of amino groups conjugated was insufficient to produce the charge effect.

Distribution of leukocytes labeled with In-111 oxine in dogs with acute inflammatory lesions.

The biodistributions of In-111 oxine (with and without leukocyte labeling) of Ga-67 citrate and of In-111 chloride were compared in 30 dogs with chemical and bacterial abscesses and acute joint inflammation. Serial blood samples were taken and tissues radioassayed at 24 hr. The concentration of In-111-oxine leukocytes in all three types of inflammatory lesion was invariably much higher than that of Ga-67 injected simultaneously. For bacterial abscesses, the mean abscess-to-muscle concentration ratio was 3,000 for labeled leukocytes and 72 for Ga-67. Aqueous buffered In-111 oxine sulfate solution appeared better for labeling leukocytes than In-111 oxine in ethanol. When In-111 oxine was not incubated with leukocytes before injection, or if the cells were poorly labeled or damaged, the abscess localization was often inferior to that of gallium. Localization of In-111 chloride also appeared inferior to that of gallium. No significant difference in distribution in the major organs or inflammatory lesions was demonstrable between labeled suspensions of "pure"neutrophils harvested by elutriation and "mixed"cell suspensions of leukocytes after erythrocyte sedimentation with hydroxyethyl starch. For both types of leukocyte suspension labeled with In-111 oxine, the average recovery of cell-bound activity in the circulating blood at 4 hr was 32% of the administered activity, inferior to that of DFP-32. It is concluded, therefore, that In-111 oxine is a more effective agent than Ga-67 for the detection of acute focal inflammatory lesions if leukocytes are properly labeled, but current techniques are unsatisfactory for the study of neutrophil kinetics.

Changes in renal uptake of Tc-99m methylene diphosphonate (MDP) in stone-forming rats.

A pyridoxine (vitamin B6)-deficient diet in rats was used as a model of early renal lithiasis to find out if "stone-formers" could be identified from control animals by differences in the biodistribution of Tc-99m MDP. The mean renal uptake of this agent at 3 hours was about 70% higher in test animals than in controls, but there was considerable overlap between the upper limits of the normal range and lower values in "stone-formers." If these results were valid for humans, the metabolic abnormality in males with early stone-forming disease could not be identified with certainty by in vivo measurements of Tc-99m MDP renal uptake alone. However, the skeletal uptake of MDP in the "stone-forming" animals was depressed by 28 to 35%, compared with control rats. Consequently, the renal to skeletal MDP concentration ratio was invariably elevated in "stone-formers" beyond the 95 percentile normal range. Unexpectedly, 76% of the pyridoxine-deficient animals had a higher accumulation of MDP in the myocardium than the upper limit of the normal range. The pyridoxine-deficient diet induced no remarkable early changes in the biodistribution or renal clearance of I-131 Hippuran.

Experimental drug-induced changes in renal function and biodistribution of 99mTc-MDP.

Increased renal uptake of 99mTc methylene diphosphonate (MDP) was observed irregularly in rats after methotrexate, vincristine or gentamicin, administered separately. Cisplatin regularly induced a dose-related increased MDP uptake which correlated with the degree of tubular damage histologically. The augmented MDP renal uptake was not consistently accompanied by a decreased clearance of simultaneously injected I-131 Hippuran, particularly at lower drug dose levels. This observation agreed with previous evidence that the mechanisms of tubular transport of diphosphonates and organic acids like Hippuran are different. At higher dose levels, the augmented MDP uptake was accompanied by increased renal calcium, hypophosphatemia, elevated serum urea nitrogen and creatinine, and only occasional, mild hypercalcemia. The magnitude of the increased renal uptake of MDP observed could not be explained by alterations in iron metabolism or by dehydration. Drug-induced renal retention of MDP by a factor of 2 or more above normal appears to be a useful indicator of tubular damage when other parameters of renal function are sometimes normal.

Comparison of 99mTc phosphate and diphosphonate complexes in experimental renal infarcts.

The 3-hour biodistribution of 99mTc complexes of five diphosphonates (HMDP, NMMDP, DMAD, DPD, and APD), imidodiphosphonate (IDP), and pyrophosphate (PYP) was compared in rats with segmental renal infarction induced by a 1-hour occlusion of a renal artery branch. 95mTc labeled MDP was a reference substance in all animals. Three agents (APD, HMDP and IDP) had a higher infarct/normal kidney concentration ratio than MDP, the latter two by virtue of a lower content in normal kidney. HMDP, DPD, and IDP had very high liver concentrations. DPD showed relatively high concentrations in soft tissues and blood. The blood and kidney levels of PYP were higher than those of MDP but the infarct/normal kidney ratios were similar. None of the agents had a higher uptake in bone than MDP: four had a significantly lower uptake. The increased concentration of 99mTc MDP in the infarcts was readily seen in camera images one day after renal artery occlusion, but not at three or seven days. Increased diphosphonate uptake was accompanied by an influx of calcium in both cortex and medulla. The accumulation of diphosphonate in areas of infarction was not modified by infusions of verapamil or Captopril.

Effective doses to patients undergoing thoracic computed tomography examinations.

The purpose of this study was to investigate how x-ray technique factors and effective doses vary with patient size in chest CT examinations. Technique factors (kVp, mAs, section thickness, and number of sections) were recorded for 44 patients who underwent a routine chest CT examination. Patient weights were recorded together with dimensions and mean Hounsfield unit values obtained from representative axial CT images. The total mass of directly irradiated patient was modeled as a cylinder of water to permit the computation of the mean patient dose and total energy imparted for each chest CT examination. Computed values of energy imparted during the chest CT examination were converted into effective doses taking into account the patient weight. Patient weights ranged from 4.5 to 127 kg, and half the patients in this study were children under 18 years of age. All scans were performed at 120 kVp with a 1 s scan time. The selected tube current showed no correlation with patient weight (r2=0.06), indicating that chest CT examination protocols do not take into account for the size of the patient. Energy imparted increased with increasing patient weight, with values of energy imparted for 10 and 70 kg patients being 85 and 310 mJ, respectively. The effective dose showed an inverse correlation with increasing patient weight, however, with values of effective dose for 10 and 70 kg patients being 9.6 and 5.4 mSv, respectively. Current CT technique factors (kVp/mAs) used to perform chest CT examinations result in relatively high patient doses, which could be reduced by adjusting technique factors based on patient size.

SU-E-I-49: Influence of Scanner Output Measurement Technique on KERMA Ratios in CT.

PURPOSE: KERMA ratios (RK) are defined as the ratio of KERMA measured at a specific phantom location (K) to in-air isocenter CT scanner output (KCT). In this work we investigate the impact of measurement methodology on KCT values. METHODS: OSL dosimeter chips were used to measure KCT for a GE VCT scanner (GE Medical Systems, Waukesha WI), using the 40 mm nominal beam width. Methods included a single point measurement at the center of the beam (1 tube rotation), and extended z-axis measurements using multiple adjacent OSL's (7.5 cm extent), with single tube rotation, multiple contiguous axial scans, and helical scans (pitch of 1.375). Measurements were made in air and on the scan table at 80 and 120 kV. RESULTS: Averaged single point measurements were consistent, with a mean coefficient of variation of 2.5%. For extended measurements with a single tube rotation, the mean value was equivalent to the single point measurements. For multiple contiguous axial scans, the in-air KCT values were higher than the single rotation mean value and single point measurements by 13% and 10.3% at 120 and 80 kV, respectively, and for the on-table measurements the values were 14.9% and 8.1% higher at 120 and 80 kV, respectively. The increase is due to beam overlap caused by z- axis over-beaming. Extended measurements using helical scanning were equivalent to the multiple rotation axial measurements when corrected for the helical pitch. For all methodologies, the in-air values exceeded the on- table measurements by an average of 23% and 19.4% at 80 and 120 kV, respectively. CONCLUSIONS: Scanner KCT values must be measured to allow organ dose estimation using published RK values. It is imperative that the KCT measurement methodology is the same as for the published values, or large errors may be introduced into the resulting organ dose estimates.