iRENEX: a clinically informed decision support system for the interpretation of 99mTc-MAG3 scans to detect renal obstruction

Purpose

Decision support systems for imaging analysis and interpretation are rapidly being developed and will have an increasing impact on the practice of medicine. RENEX is a renal expert system to assist physicians evaluate suspected obstruction in patients undergoing mercaptoacetyltriglycine (MAG3) renography. RENEX uses quantitative parameters extracted from the dynamic renal scan data using QuantEM?II and heuristic rules in the form of a knowledge base gleaned from experts to determine if a kidney is obstructed; however, RENEX does not have access to and could not consider the clinical information available to diagnosticians interpreting these studies. We designed and implemented a methodology to incorporate clinical information into RENEX, implemented motion detection and evaluated this new comprehensive system (iRENEX) in a pilot group of 51 renal patients.

Methods

To reach a conclusion as to whether a kidney is obstructed, 56 new clinical rules were added to the previously reported 60 rules used to interpret quantitative MAG3 parameters. All the clinical rules were implemented after iRENEX reached a conclusion on obstruction based on the quantitative MAG3 parameters, and the evidence of obstruction was then modified by the new clinical rules. iRENEX consisted of a library to translate parameter values to certainty factors, a knowledge base with 116 heuristic interpretation rules, a forward chaining inference engine to determine obstruction and a justification engine. A clinical database was developed containing patient histories and imaging report data obtained from the hospital information system associated with the pertinent MAG3 studies. The system was fine-tuned and tested using a pilot group of 51 patients (21 men, mean age 58.2?±?17.1?years, 100 kidneys) deemed by an expert panel to have 61 unobstructed and 39 obstructed kidneys.

Results

iRENEX, using only quantitative MAG3 data agreed with the expert panel in 87?% (34/39) of obstructed and 90?% (55/61) of unobstructed kidneys. iRENEX, using both quantitative and clinical data agreed with the expert panel in 95?% (37/39) of obstructed and 92?% (56/61) of unobstructed kidneys. The clinical information significantly (p?Conclusion Our renal expert system for detecting renal obstruction has been substantially expanded to incorporate the clinical information available to physicians as well as advanced quality control features and was shown to interpret renal studies in a pilot group at a standardized expert level. These encouraging results warrant a prospective study in a large population of patients with and without renal obstruction to establish the diagnostic performance of iRENEX.     

A software engine to justify the conclusions of an expert system for detecting renal obstruction on 99mTc-MAG3 scans.

The purposes of this study were to describe and evaluate a software engine to justify the conclusions reached by a renal expert system (RENEX) for assessing patients with suspected renal obstruction and to obtain from this evaluation new knowledge that can be incorporated into RENEX to attempt to improve diagnostic performance. METHODS: RENEX consists of 60 heuristic rules extracted from the rules used by a domain expert to generate the knowledge base and a forward-chaining inference engine to determine obstruction. The justification engine keeps track of the sequence of the rules that are instantiated to reach a conclusion. The interpreter can then request justification by clicking on the specific conclusion. The justification process then reports the English translation of all concatenated rules instantiated to reach that conclusion. The justification engine was evaluated with a prospective group of 60 patients (117 kidneys). After reviewing the standard renal mercaptoacetyltriglycine (MAG3) scans obtained before and after the administration of furosemide, a masked expert determined whether each kidney was obstructed, whether the results were equivocal, or whether the kidney was not obstructed and identified and ranked the main variables associated with each interpretation. Two parameters were then tabulated: the frequency with which the main variables associated with obstruction by the expert were also justified by RENEX and the frequency with which the justification rules provided by RENEX were deemed to be correct by the expert. Only when RENEX and the domain expert agreed on the diagnosis (87 kidneys) were the results used to test the justification. RESULTS: RENEX agreed with 91% (184/203) of the rules supplied by the expert for justifying the diagnosis. RENEX provided 103 additional rules justifying the diagnosis; the expert agreed that 102 (99%) were correct, although the rules were considered to be of secondary importance. CONCLUSION: We have described and evaluated a software engine to justify the conclusions of RENEX for detecting renal obstruction with MAG3 renal scans obtained before and after the administration of furosemide. This tool is expected to increase physician confidence in the interpretations provided by RENEX and to assist physicians and trainees in gaining a higher level of expertise.     

Diagnostic performance of an expert system for interpretation of 99mTc MAG3 scans in suspected renal obstruction.

The purpose of the study was to compare diuresis renography scan interpretation generated by a renal expert system with the consensus interpretation of 3 expert readers. METHODS: The expert system was evaluated in 95 randomly selected furosemide-augmented patient studies (185 kidneys) obtained for suspected obstruction; there were 55 males and 40 females with a mean age +/- SD of 58.6 +/- 16.5 y. Each subject had a baseline (99m)Tc-mercaptoacetyltriglycine ((99m)Tc-MAG3) scan followed by furosemide administration and a separate 20-min acquisition. Quantitative parameters were automatically extracted from baseline and furosemide acquisitions and forwarded to the expert system for analysis. Three experts, unaware of clinical information, independently graded each kidney as obstructed/probably obstructed, equivocal, and probably nonobstructed/nonobstructed; experts resolved differences by a consensus reading. These 3 expert categories were compared with the obstructed, equivocal, and nonobstructed interpretations provided by the expert system. Agreement was assessed using weighted kappa, and the predictive accuracy of the expert system compared with expert readers was assessed by the area under receiver-operating-characteristic (ROC curve) curves. RESULTS: The expert system agreed with the consensus reading in 84% (101/120) of nonobstructed kidneys, in 92% (33/36) of obstructed kidneys, and in 45% (13/29) of equivocal kidneys. The weighted kappa between the expert system and the consensus reading was 0.72 and was comparable with the weighted kappa between experts. There was no significant difference in the areas under the ROC curves when the expert system was compared with each expert using the other 2 experts as the gold standard. CONCLUSION: The renal expert system showed good agreement with the expert interpretation and could be a useful educational and decision support tool to assist physicians in the diagnosis of renal obstruction. To better mirror the clinical setting, algorithms to incorporate clinical data must be designed, implemented, and tested.     

Relative 99mTc-MAG3 renal uptake: reproducibility and accuracy.

The aim of this study was to estimate the reproducibility and accuracy of 99mTc-mercaptoacetyltriglycine (MAG3) relative percentage uptake. METHODS: Reproducibility was evaluated on healthy volunteers who were submitted twice to a 99mTc-MAG3 renographic study, which used different uptake algorithms, different background corrections and different time intervals. Accuracy was evaluated in a group of patients with symmetrical or asymmetrical relative renal function, who underwent both 99mTc-dimercaptosuccinic acid (DMSA) and 99mTc-MAG3 studies, using the DMSA relative percentage uptake as a reference. RESULTS AND CONCLUSION: The methods that combined the best reproducibility and accuracy for estimating 99mTc-MAG3 left-to-right uptake ratio were the integral method, with subrenal or perirenal background correction, and the Patlak-Rutland plot. The use of the integral method without background correction introduced a systematic bias, whereas the slope method resulted in high variability. Therefore these methods cannot be recommended.     

99mTc-MAG3: dynamic studies in patients with renal disease

Animal studies have suggested that 99mTc-mercapto-acetylglycyl-glycyl-glycine (99mTc-MAG3) might be suitable for the determination of the renal plasma flow (RPF) because of its high renal clearance. In this study 131I-orthoiodohippurate (131I-OIH) and 99mTc-MAG3 (labeling always greater than 95%) were administered simultaneously in 11 patients (creatinine clearance ranging from 14 to 130 ml/min per 1.73 m2) to measure effective RPF(ERPF) using the standard technique (UV/P). Glomerular filtration rate (GFR; clearance of 125I-thalamate, 125I-OT) was also measured. The mean ratio of 99mTc-MAG3 clearance to 131I-IOH clearance was 0.55 +/- 0.02 (SEM), P less than 0.01, n = 16, and was independent of GFR and ERPF. To study this difference in renal handling of the radiopharmaceuticals, renal extractions by the right kidney were determined in another six patients after a single shot of the agents. Renal extraction of 99mTc-MAG3 was 0.60 +/- 0.03 after 5 min, and 0.41 +/- 0.08 after 30 min. Renal extraction of 131I-OIH amounted to 0.86 +/- 0.04 and 0.77 +/- 0.03, respectively. Using renal extractions of 0.41 and 0.77, respectively, it appeared that calculated renal plasma flows measured simultaneously with 99mTc-MAG3 and 131I-OIH were similar. Protein binding 30 min after the priming dose was 66% for 99mTc-MAG3 and 47% for 123I-OIH. We conclude that in spite of a high renal clearance (ratio to 125I-OT clearance 2.69 +/- 0.27), 99mTc-MAG3 seems unsuitable for an accurate determination of the RPF.(ABSTRACT TRUNCATED AT 250 WORDS)     

99mTc-MAG3: Dynamic studies in patients with renal disease

Animal studies have suggested that ^99mTc-mercapto-acetylglycyl-glycyl-glycine (^99mTc-MAG3) might be suitable for the determination of the renal plasma flow (RPF) because of its high renal clearance. In this study ¹³¹I-orthoiodohippurate (¹³¹I-OIH) and ^99mTc-MAG3 (labeling always >95%) were administered simultaneously in 11 patients (creatinine clearance ranging from 14 to 130 ml/min per 1.73 m²) to measure effective RPF(ERPF) using the standard technique (UV/P). Glomerular filtration rate (GFR; clearance of ¹²⁵I-thalamate, ¹²⁵I-OT) was also measured. The mean ratio of ^99mTc-MAG3 clearance to ¹³¹I-IOH clearance was 0.55±0.02 (SEM), P<0.01, n=16, and was independant of GFR and ERPF. To study this difference in renal handling ofthe radiopharmaceuticals, renal extractions by the right kidney were determined in another six patients after a single shot of the agents. Renal extraction of ^99mTc-MAG3 was 0.60±0.03 after 5 min, and 0.41±0.08 after 30 min. Renal extraction of ¹³¹I-OIH amounted to 0.86±0.04 and 0.77±0.03, respectively. Using renal extractions of 0.41 and 0.77, respectively, it appeared that calculated renal plasma flows measured simultaneously with ^99mTc-MAG3 and ¹³¹I-OIH were similar. Protein binding 30 min after the priming dose was 66% for ^99mTc-MAG3 and 47% for ¹²³I-OIH. We conclude that in spite of a high renal clearance (ratio to ¹²⁵I-OT clearance 2.69±0.27), ^99mTc-MAG3 seems unsuitable for an accurate determination of the RPF. This conclusion is strongly supported bythe observation that the ratio of ^99mTc-MAG3 to ¹³¹I-IOH clearance markedly decreased from 0.66 to 0.32 in a patient with an increase in urinary protein loss.     

Evaluation of renal function from 99mTc-MAG3 renography without blood sampling.

To develop a camera-based method for evaluating renal function with 99mTc-mercaptoacetyltriglycine (MAG3), we examined the relationship between various renogram parameters and 99mTc-MAG3 clearance. METHODS: Twenty-one patients underwent renal scintigraphy with 99mTc-MAG3. Eighty 3-s frames were obtained after the bolus injection of 250 MBq tracer, followed by the collection of 52 30-s frames. Regions of interest were drawn for the kidneys, perirenal background areas and subrenal background areas, and background-subtracted renograms were generated. Renal accumulation at 0.5-1.5, 0.5-2, 1-2, 1-2.5 and 1.5-2.5 min after tracer arrival in the kidney was calculated as area under the background-subtracted renogram, and percent renal uptake was obtained after correction for soft-tissue attenuation and injected dose. The slope of the renogram was determined for the same segments used in calculating area under the renogram, and slope index was computed as slope corrected for attenuation and injected dose. Percent renal uptakes and slope indices were correlated by linear regression analysis with 99mTc-MAG3 clearance measured using a single blood sampling method. RESULTS: Among the values of percent renal uptake, the value obtained at 1.5-2.5 min using the perirenal background correlated best with 99mTc-MAG3 clearance. The slope index at 0.5-1.5 or 0.5-2 min using the subrenal background provided better accuracy than percent renal uptake for predicting clearance. There were no substantial differences in the relative function of the right kidney between the methods using percent renal uptake and slope index. CONCLUSION: 99mTc-MAG3 clearance can be assessed with acceptable accuracy by a camera-based method. The method based on the slope of the renogram may replace the one based on the area under the renogram in evaluating renal function from 99mTc-MAG3 renograms.     

A Bayesian 3-compartment model for 99mTc-MAG3 clearance.

Because recent reports have questioned the traditional 2-compartment model for calculating tracer clearance after a single intravenous injection, a 3-compartment model was evaluated in this study. METHODS: Bayesian statistics were used, which facilitated curve fitting by treating all subjects simultaneously. (99m)Tc-Mercaptoacetyltriglycine clearance data from 154 adults and 109 children were measured at several centers, typically 6-9 plasma samples spanning 5-90 min, and fitted by 2- and 3-compartment Bayesian models. RESULTS: Clearance estimates were found to be systematically lower for the 3-compartment model than for the 2-compartment model. A single-sample procedure based on the 3-compartment model was found to eliminate most of the known discrepancy between formulas based on single-injection and continuous-infusion reference methods. CONCLUSION: A 3-compartment model led to lower and probably more accurate clearance estimates than the conventional 2-compartment model. A new single-sample method is presented, based on the 3-compartment model as reference standard.     

99mTc-MAG3: Review of pharmacokinetics, clinical application to renal diseases and quantification of renal function

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.     

Evaluation of renal function with 99mTc-MAG3 using semiautomated regions of interest.

The need to draw regions of interest (ROIs) manually may reduce the convenience and reliability of estimating renal function from renal scintigraphy. We developed a semiautomated method to define ROIs for renal scintigraphy with 99mTc-mercaptoacetyltriglycine (MAG3) and evaluated the clinical applicability of the method to the estimation of renal function by camera-based methods. METHODS: Dynamic renal scintigraphy with 99mTc-MAG3 was performed on 21 patients. An operator placed a large rectangular ROI over each kidney, a circular ROI within the liver, and a rectangular ROI between the kidneys. Using these ROIs, semiautomated renal ROIs were determined on the basis of the temporal changes in counts, in addition to the absolute counts, and a subrenal background ROI was automatically assigned for each renal ROI. Background-subtracted renograms were generated using these renal and subrenal ROIs, and renogram parameters were derived from the slope of the renogram and the area under the renogram. Clearance was calculated using the renogram parameters and equations determined previously with manual ROIs and correlated with clearance measured by a single-sample method. The relative function of the right kidney determined by the semiautomated method was compared with that determined by the manual method. Data processing was performed independently by another operator to assess interoperator reproducibility. RESULTS: ROIs defined by the semiautomated method were visually judged to be acceptable for clinical use in all patients with a wide range of renal function. Clearance was successfully predicted with the semiautomated ROIs (r = 0.968 using the slope of the renogram; r = 0.934 using the area under the renogram), and relative function calculated with the semiautomated ROIs was almost identical to that calculated with manual ROIs. There was almost complete concordance in absolute and relative function between the two operators. CONCLUSION: The semiautomated method can define ROIs for 99mTc-MAG3 renal scintigraphy with limited operator intervention. Camera-based methods using the semiautomated ROIs allow estimation of renal function with high accuracy and little interoperator variability and are suggested to be suitable for clinical use.     

Technetium-99m labeled renal function and imaging agents: III. Synthesis of 99mTc-MAG3 and biodistribution of by-products

^99mTc-MAG₃, a new ^99mTc radiopharmaceutical with biological properties similar to o-iodohippuric acid (OIH), is expected to find wide clinical application for renal function studies. Therefore it is important to make a kit formulation available which provides reproducibly the desired product in high radiochemical yields.Some differences between the biokinetic data of kit prepared ^99mTc-MAG₃ and HPLC-purified ^99mTc-MAG₃ were reported by different authors. The subject of this paper is the isolation of the by-products which are formed with our own kits, the evaluation of their biological behaviour and the comparison with the main product ^99mTc-MAG₃ in rats.The results suggest that the radiochemical purity of ^99mTc-MAG₃-preparations should be not less than 95%.     

99mTc-MAG3, a new renal imaging agent: Preliminary results in patients

^99mTc-mercaptoacetyltriglycine (MAG₃) is a new renal radiopharmaceutical which has been shown to have biological properties similar to¹³¹I-hippurate (OIH) in animals and volunteers.^99mTc-MAG₃ has now been compared with¹³¹I-orthoiodohippurate (OIH) in a group of patients with varying degrees of renal impairment. In all cases, the^99mTc-MAG₃ images were superior regardless of serum creatinine. Selected examples are illustrated including scans and renogram curves in a normal volunteer, transplant patients with creatinines of 9.8 mg/dl and 2.6 mg/dl respectively, and a furosemide study in a patient with questionable obstruction. Our preliminary results suggest that^99mTc-MAG₃ performs well in patients with impaired renal function and may well provide an acceptable replacement for OIH. A kit formulation has been developed and will soon be undergoing clinical evaluation.     

Validation of alternative methods of preparing 99mTc-MAG3.

Parameters in the preparation of 99mTc-mertiatide (99mTc-MAG3) were investigated to determine the importance of total activity, activity concentration, boiling time, and delay before boiling for the radiochemical purity (RCP) and stability of the product. Satisfactory RCP results (>90%) were obtained over a range of concentrations including a dilute preparation for paediatric use. RCP was not affected by the time between the addition of pertechnetate and boiling, but low RCP (<60%) resulted when the kit was boiled for less than 10 min.     

Preparation of the renal function and imaging agent 99mTc-MAG3 starting from S-unprotected mercaptoacetyltriglycine

A new approach that obviates inconvenient heating of the labelling solution when preparing the renal function and imaging agent ^99mTc-MAG₃ is described. The labelling procedure involves reduction of ^99mTc-generator eluate with stannous chloride in alkaline solution in the presence of S-unprotected mercaptoacetyltriglycine (MAG₃) and the co-ligand sodium tartrate, followed by neutralization with a phosphate buffer solution. After optimization of the kit preparation the radiochemical purity of the radiopharmaceutical amounts to > 98%. During the labelling process intermediate Tc-species occur.