Two routes for 99mTc-DMSA uptake into the renal cortical tubular cell

Critical factors determining the renal handling of 99mTc-dimercaptosuccinic acid (DMSA) are protein binding in plasma and the renal 99mTc-DMSA extraction efficiency. Comparison of the count rate over soft tissue with that over the cardiac blood pool about 1 h after injection demonstrated that 99mTc-DMSA is not exclusively an intravascular label. 99mTc-DMSA was 76% protein bound in plasma as demonstrated by HPLC and gel filtration. Assuming that the 24% that is not protein bound is filtered at the glomerulus, the renal extraction efficiency of 99mTc-DMSA by glomerular filtration is about 5%. Since the total renal extraction efficiency was also found to be about 5%, the majority of the activity that becomes fixed in the renal cortex arrives there as a result of filtration followed by tubular reabsorption rather than by direct extraction from peritubular blood. However, discordant changes in DMSA and DTPA uptake induced by captopril in renovascular hypertension (RVH) suggested that a minority of uptake was by direct peritubular extraction. This kinetic model was supported by indirect measurement of protein binding and extraction efficiency based on the kinetics of 99mTc-DMSA disappearance from plasma and kinetics of uptake in the kidneys. Furthermore, differential functional studies based on 99mTc-DMSA and 99mTc-DTPA before and after captopril in patients with RVH due to unilateral renal artery stenosis confirmed filtration followed by tubular reabsorption as the predominant route for DMSA uptake by the kidney.     

Renal uptake of dimercaptosuccinic acid and glomerular filtration rate in chronic nephropathy at angiotensin converting enzyme inhibition

Glomerular filtration rate (GFR) and renal uptake of dimercaptosuccinic acid (DMSA) were measured in 31 patients with progressive chronic nephropathy before and immediately after the start of treatment with angiotensin converting enzyme (ACE) inhibitor in order to control adverse effects on kidney function. Scintigrams of the kidneys showed an unaltered distribution of DMSA during treatment. GFR estimated by⁵¹Cr-EDTA plasma clearance fell by 14% (P < 0.01), but renal uptake of^99mTc-DMSA increased by 10% (P < 0.01). It is concluded that DMSA in chronic renal failure is mainly taken up by the tubular cells from the peritubular capillaries since the uptake was unaffected by the acute decrease in GFR.     

A kinetic model for99mTc-DMSA in the rat

A pharmacokinetic model was developed for the renal imaging agent^9mTc-DMSA in anesthetized rats, which incorporated data from serial measurements of blood and urine simultaneously with dynamic images obtained over an 8-h period. Animals which received a 10 mg/kg dose of unlabeled DMSA immediately before^99mTc-DMSA injection had a significantly reduced kidney accumulation and greater urinary elimination of^99mTc than animals which received the radiopharmaceutical alone. The kidney clearance was also significantly lower in rats receiving unlabeled DMSA, but no significant difference was determined between the urine clearance estimates of the two animal groups. Because the increase in the amount eliminated in the urine was not coupled with a significant change in urine clearance, it would appear that unlabeled DMSA saturated the kidney uptake mechanism(s) of^99mTc-DMSA without modifying the urinary clearance process. This interpretation is consistent with the hypothesis that renal handling of^99m'Tc-DMSA is governed by both glomerular filtration and peritubular capillary uptake. The simultaneous acquisition of blood, urine and non invasive image data allows for a comprehensive and informative model of the physiological disposition of^99mTc-DMSA.     

Reversible diminished renal 99mTc-DMSA uptake during converting-enzyme inhibition in a patient with renal artery stenosis

A patient is described who had accelerated hypertension and unilateral renal artery stenosis, and who developed further deterioration in renal function during treatment with captopril, an angiotension-I (AI) converting-enzyme inhibitor. ^99mTc-DMSA uptake was greatly diminished in the stenotic kidney, although renal blood flow and handling of ¹³¹I-hippurate was preserved. Uptake of ^99mTc-DMSA in the affected kidney returned after substitution of captopril by the vasodilator minoxidil, while a comparable degree of blood pressure control was maintained.Thus, caution must be taken when interpreting results of ^99mTc-DMSA scintigraphy in patients with proven or suspected renal artery stenosis treated with an AI converting-enzyme inhibiting drug. Moreover, our finding points to the importance of glomerular filtration in the renal handling of ^99mTc-DMSA.     

Renal handling of technetium-99m DMSA: evidence for glomerular filtration and peritubular uptake

The finding of an enhanced excretion of [99mTc]dimercaptosuccinic acid (DMSA) in patients with tubular reabsorption disorders prompted us to investigate the role of filtration in the renal handling of [99mTc]DMSA. Our studies in human serum indicated that binding to serum proteins was approximately 90%. Chromatography of human urine and studies in rats showed that the complex was excreted unaltered into the urine. Renal extraction of [99mTc]DMSA in a human volunteer was 5.8%. Continuous infusion of [99mTc]DMSA in 13 individuals with normal renal function gave the following results (mean +/- s.d.): plasma clearance of [99mTc]DMSA 34 +/- 4 ml/min, urinary clearance of [99mTc]DMSA 12 +/- 3 ml/min. The calculated filtered load of [99mTc]DMSA closely resembled the urinary clearance, whereas the plasma clearance was about three times faster. This indicates that peritubular uptake accounts for approximately 65% and filtration for approximately 35% of the renal handling of [99mTc]DMSA.     

Single-photon emission CT using 99mTc-dimercaptosuccinic acid (DMSA) for characterization of suspected renal masses

Objective:

A retrospective analysis of the clinical utility of ^99mTc-dimercaptosuccinic acid (DMSA) single photon emission CT (SPECT) for characterization of suspected renal masses.

Methods:

15 patients who had undergone ^99mTc-DMSA SPECT were identified, and 13 patients also had SPECT/CT. ^99mTc-DMSA uptake in the renal lesion was characterized semiquantitatively. Other imaging tests, histology and clinical data were available for correlation.

Results:

^99mTc-DMSA was not taken up in all five renal masses with histological confirmation of malignancy (uptake 7–19% of normal renal tissue); in two further masses, which were clinically likely to be malignant; and in one indeterminate mass (lack of sufficiently long follow-up). No renal malignancy was identified in any of the seven patients whose renal masses had normal ^99mTc-DMSA uptake (41–130%).

Conclusion:

Although caution with regard to applying those results in clinical practice must be advised, owing to the retrospective nature of this report and the small number of patients included, it seems that ^99mTc-DMSA SPECT shows a clinically useful diagnostic accuracy for distinguishing true renal masses (which in many cases require surgery) from pseudomasses.

Advances in knowledge:

^99mTc-DMSA SPECT is a clinically useful adjunct test for characterization of suspected renal masses.^99mTc-labelled 2,3-dimercaptosuccinic acid (DMSA) has been the standard radiopharmaceutical for static renal scintigraphy for many years.¹ It has a high degree of plasma protein binding (76%). Its main metabolic pathway first involves glomerular filtration, followed by tubular reabsorption, with minimal urinary excretion (5%).² In adults, its foremost clinical use is to determine differential renal function, but also to image ectopic renal tissue.³We have occasionally used ^99mTc-DMSA scans to establish whether a suspected renal mass or pseudomass contains functioning renal tissue or not. Such use is acknowledged in a respected textbook,⁴ stating that “for many years ^99mTc-DMSA with or without single-photon emission CT (SPECT) was used as a problem-solving technique to differentiate a space-occupying solid mass from a column of Bertin…”. However, we were surprised to be able to identify only a small number of publications reporting the use of ^99mTc-DMSA SPECT for this purpose in a series of patients.^5,6This article reports the results of ^99mTc-DMSA SPECT in 15 patients referred for evaluation of a suspected renal mass from our case archive.     

The utility of (99m)Tc-DMSA and Tc(99m)-EC scintigraphy for early diagnosis of ifosfamide induced nephrotoxicity.

A serious undesired effect of certain cytostatics is their nephrotoxicity. In this study, we investigated the toxic effects of ifosfamide and cisplatin by clinical and biochemical parameters in relation to (99m)Tc-dimercaptosuccinic acid ((99m)Tc-DMSA) and Tc(99m)N, N-ethylenedicysteine (EC) renal scintigraphy. The indicators were urinary beta2-microglobulin levels, tubular resorption of phosphate, urinary protein and glucose excretion, glomerular filtration rate, urinary pH and osmolarity. Thirteen paediatric patients (seven boys and six girls), aged 2-16 years, were investigated. Five patients received only cisplatin, six patients were treated with ifosfamide and cisplatin and two with ifosfamide and carboplatin for various malignancies. All except three patients had normal DMSA uptake (median, 19; range, 16-29%) prior to chemotherapy. The reduction in DMSA uptake was unilateral due to tumour invasion in those three patients. Following chemotherapy, DMSA uptake showed reduction in five patients with or without clinical nephrotoxicity. The observed pattern was decreased renal uptake and elevated bladder activity. Three patients with decreased DMSA uptake had normal tubular maximum phosphate reabsorption, which suggested subclinical injury. Decrease in DMSA uptake and tubular phosphate reabsorption (TPR) was detected simultaneously in two patients. No abnormalities were seen on Tc(99m)-EC scintigraphy to suggest nephrotoxicity in our investigation. However, Tc(99m)-EC clearly demonstrated a reduction in split renal function in children with tumour invasion. In summary, we found that ifosfamide induced tubular injury can be detected with (99m)Tc-DMSA scintigraphy before chemotherapy associated nephrotoxicity is observed by laboratory measurements. Our results also imply that, although a tubular agent, renal scintigraphy performed with Tc(99m)-EC is not able to detect subclinical injury or predict the outcome during treatment.     

Technetium-99m dimercaptosuccinic acid and ifosfamide tubular dysfunction in children with cancer

Quantitative ^99mTc-dimercaptosuccinic acid (^99mTc-DMSA) renal scintigraphy was used to asses ifosfamide-induced changes in renal function in 11 children who received chemotherapy for various malignancies. Serial measurements of absolute ^99mTc-DMSA renal uptake, calculated on conjugated views, were performed during and after chemotherapy. Data of 37 studies obtained before and at different cumulative dose levels of ifosfamide were analysed in relation to clinical and biochemical parameters. A highly significant relationship between ^99mTc-DMSA uptake and cumulative ifosfamide dose was found (P<0.001). The most frequently observed abnormal pattern on scintigraphic images was decreased kidney uptake together with increased accumulation in bladder. ^99mTc-DMSA uptake was more consistent than ₂-microglobulin values in urine and more sensitive than quantitative hyperaminoaciduria and tubular resorption of phosphate for the detection of ifosfamide-induced tubular dysfunction. ^99mTc-DMSA uptake was decreased in both patients with and patients without clinical toxicity. Persistently reduced ^99mTc-DMSA uptake was observed in four patients during follow-up; in one of them, who was asymptomatic after ifosfamide therapy, sudden onset of Fanconi syndrome was observed when he was retreated with carboplatin 1 year later. It is concluded that ^99mTc-DMSA renal scintigraphy is a suitable method to assess progressive ifosfamide-induced tubular injury whereas scintigraphic imaging is helpful for interpreting renal uptake changes. The test is able to detect subclinical injury and may potentially predict high risk at retreatment.     

Low renal uptake of 99mTc-DMSA in patients with proximal tubular dysfunction

In nine patients with different types of proximal tubulopathy and a nearly normal glomerular filtration rate a low uptake of ^99mTc-DMSA in the kidneys was found. The underlying mechanism seems to be an increased urinary excretion of ^99mTc-DMSA. This radiopharmaceutical might be used as a marker of proximal tubular dysfunction.     

Renal uptake of dimercaptosuccinic acid and glomerular filtration rate in chronic nephropathy at angiotensin converting enzyme inhibition

Glomerular filtration rate (GFR) and renal uptake of dimercaptosuccinic acid (DMSA) were measured in 31 patients with progressive chronic nephropathy before and immediately after the start of treatment with angiotensin converting enzyme (ACE) inhibitor in order to control adverse effects on kidney function. Scintigrams of the kidneys showed an unaltered distribution of DMSA during treatment. GFR estimated by 51Cr-EDTA plasma clearance fell by 14% (P less than 0.01), but renal uptake of 99mTc-DMSA increased by 10% (P less than 0.01). It is concluded that DMSA in chronic renal failure is mainly taken up by the tubular cells from the peritubular capillaries since the uptake was unaffected by the acute decrease in GFR.     

Oxygen bubbling can improve the labelling of pentavalent technetium-99m dimercaptosuccinic acid

It has previously been reported that almost all of the trivalent technetium-99m dimercaptosuccinic acid (^99mTc (III) DMSA) present in the labelling product of pentavalent technetium-99m DMSA (^99mTc (V) DMSA) can be changed into^99mTc (V) DMSA by bubbling with pure oxygen. We therefore performed studies in animals (mice) and humans to investigate the effect of such oxygen bubbling on the labelling efficiency of and on the renal uptake of^99mTc. The method of labelling of^99mTc (V) DMSA was that of Hirano. It was found that oxygen bubbling oxidized the contaminated^99mTc (III) DMSA into^99mTc (V) DMSA in vitro and decreased the uptake of radioactivity in the kidney in both animals and humans.     

Is the relative99mTc-DMSA clearance a useful marker of proximal tubular dysfunction?

The clearance of¹²⁵I-sodium iothalamate,¹³¹I-sodium hippurate,^99mTc-DMSA, and ₂-microglobulin were determined in 20 patients with proven or suspected proximal tubular dysfunction and in 18 control patients with various renal diseases. A clear distinction in the relative^99mTc-DMSA clearance was observed between patients with proximal tubulopathy (14%–35%) and control patients (>14%). A similar difference between the two groups was found in the relative ₂-microglobulin clearance. Nine patients with proximal tubulopathy showed an elevated filtration fraction versus only two control patients. The renal handling of^99mTc-DMSA seems to be an indicator of proximal tubular function.     

Normal appearances of technetium-99m dimercaptosuccinic acid in children on planar imaging

Thirty-two children who underwent renal arteriography with normal results also underwent technetium-99m dimercaptosuccinic acid (DMSA) imaging. Variations in the normal appearance of ^99mTc-DMSA images are described in these children. Criteria for high-quality ^99mTc DMSA images are defined in terms of kidney outline and contrast between the inner and the outer part of the kidney. Most of the images in this study were of high quality. The two most common features of normal ^99mTc-DMSA images were a round-shaped (50%) or flat (either lateral or medial aspect) (24.8%) contour. A small number of unusual appearances were observed and these have been illustrated. The mean differential function of the left kidney was 51% with a range of 45%–57%. Received 9 October 1998 and in revised form 5 January 1999     

The effect of radiopharmaceutical choice on the assessment of the relative renal function in upper urinary tract obstruction

The relative function of the obstructed kidney (RFOK) was assessed in 43 adult patients with upper urinary tract obstruction (UUTO) using ^99mTc-DTPA and ¹³¹I-ortho-iodohippurate (OIH) dynamic studies and ^99mTc-DMSA dynamic and static studies. The patients were divided into five groups according to the duration and degree of obstruction. Findings were as follows: a) in patients with the first occurrence of acute severe obstruction (group 1), the relative glomerular filtration rate (GFR) was significantly less than the relative effective renal plasma flow (ERPF); b) in patients with chronic severe obstruction and long term uroinfection, the relative ERPF decreased significantly compared with the relative GFR; c) the RFOK calculated from the DMSA dynamic study was the same as both the relative GFR or ERPF in any group; d) the RFOK calculated from the DMSA static study seemed to parallel the relative ERPF more closely than the relative GFR, but in group one it was significantly higher than any of three other estimates. It is concluded that ^99mTc-DTPA is the radiopharmaceutical of choice in obstructive uronephropathy, but when interpreting the RFOK, the time course and severity of obstruction, the presence or absence of uroinfection should also be considered.     

In vivo estimation of renal volume using a rotating gamma camera for 99mTc-dimercaptosuccinic acid renal imaging

The in vivo renal volume was determined using SPECT for ^99mTc-DMSA renal imaging. The total renal volume was derived by summing the DMSA distribution volumes of the transaxial slices in the whole kidney. In 20 healthy subjects the renal volume in the right kidney was 220 ml for men and 195.2 ml for women, while that in the left kidney was 213 ml for men and 193.7 ml for women. Differences in those values were not statistically significant. A good correlation was found between renal volumes in both kidneys and body surface area. In 106 kidneys including solitary and pathological kidneys, individual renal volume correlated well with individual DMSA renal uptake rate which demonstrates cortical functioning mass, depending on the cortical blood flow. Thus, SPECT enables an accurate noninvasive means of estimating in vivo functioning renal volume.     

Renal handling of technetium-99m DMSA in rats with proximal tubular dysfunction

The renal handling of technetium-99m dimercaptosuccinic acid ([99mTc]DMSA) was studied in rats before and after treatment with Na-maleate (2 mmol/kg i.v.). In the control period, when measured 2 hr after the intravenous injection of [99mTc]DMSA, 39.9% of the injected dose was in the kidneys and 14.6% was in the bladder. After Na-maleate treatment, only 6.4% of the injected dose of [99mTc]DMSA was retained in the kidneys while 37.9% was found in the bladder. Subsequent studies revealed that Na-maleate produced a fall in the glomerular filtration rate, the effective renal plasma flow, and a generalized proximal tubular dysfunction. The latter was characterized by polyuria and an increased excretion of glucose, protein, albumin, calcium, and inorganic phosphate. It was concluded that proximal tubular dysfunction markedly alters the renal handling of [99mTc]DMSA. Whether this augmented urinary excretion is due to an inhibition of reabsorption or an enhanced cellular efflux of [99mTc]DMSA remains to be answered.     

Differences between99mTc-DTPA and99mTc-MAG3 captopril renographies in renovascular hypertension

Captopril renography (CRS) with^99mTc-DTPA and^99mTc-MAG3 was performed on a 21-year-old woman with renovascular hypertension due to right renal artery stenosis caused by fibromuscular dysplasia. In the affected kidney, the renogram pattern was substantially changed with^99mTc-DTPA and^99mTc-MAG3 following the administration of captopril, and the quantitated renal uptake indicating individual renal function was significantly decreased in^99mTc-DTPA and slightly decreased in^99mTc-MAG3. In the contralateral normal kidney, the renogram showed some minor changes with both radioagents, while the quantitated renal uptake was significantly decreased with^99mTc-DTPA and substantially increased with^99mTc-MAG3. The combined use of physiologically different renal agents^99mTc-DTPA and^99mTc-MAG3 is helpful in investigating hemodynamic and functional changes in the stenosed kidney as well as the normal kidney in RVH.     

Complete and partial ureteral obstruction: evaluation of renal effects with P-31 MR spectroscopy and Tc-DMSA scintigraphy

Phosphorus-31 magnetic resonance (MR) spectroscopy was used to study the effects of partial and complete ureteral obstruction on the porcine kidney; results were compared with renal tubular function as determined with technetium-99m dimercaptosuccinic acid (DMSA) scintigraphy. Twenty-seven pigs were used: nine as sham-operated controls, six with partial ureteral obstruction, and 12 with complete ureteral obstruction. P-31 MR spectra and Tc-DMSA scintiscans were obtained weekly over 3 weeks. Partial obstruction caused no significant change in P-31 MR spectra, whereas Tc-DMSA scintiscans showed a 74% decrease in tubular function by the end of 3 weeks. Complete obstruction caused a 43% reduction in the mean adenosine triphosphate (ATP) to inorganic phosphate (Pi) ratio, which paralleled the 96% decrease in Tc-DMSA uptake over 3 weeks. The difference in ATP/Pi ratios between control and completely obstructed kidneys was significant (P less than .01) at 2 and 3 weeks after ligation. These results indicate that radionuclide Tc-99m DMSA uptake is very sensitive to the pathophysiologic changes in renal tubular function, while the organ average cellular bioenergetic state (ATP/Pi) is not as strongly affected.     

99mTc-DTPA and 99mTc-DMSA renal gamma imaging in the surveillance of patients with conduit urinary diversion

We studied renal anatomy and function using ^99mTc-2-3 dimercaptosuccinic acid (DMSA) and ^99mTc-diethylenetriaminepentaacetic acid (DTPA) in 27 patients with conduit urinary diversion. In this condition, free ureteral reflux is often associated with bacteriuria, and these factors are thought to precipitate progressive renal deterioration. Gamma-camera images provided valuable information concerning the structure of the renal parenchyma, the function of individual kidneys and possible ureteral obstruction, thus helping us to decide whether or not to instigate further treatment. The information gained using renal gamma imaging with ^99mTc-DTPA and ^99mTc-DMSA was complementary and partly overlapping. We preferred the use of ^99mTc-DTPA because of its ability to visualise the ureters and the region of ureteroconduit anastomosis. Using diuretic medication, we were able to differentiate true ureteral obstruction from atony in 9 patients using ^99mTc-DTPA.     

In vitro and in vivo studies with pentavalent technetium-99m dimercaptosuccinic acid

The purpose of this investigation was to characterise the in vivo chemistry and binding mechanisms of technetium-99m dimercaptosuccinic acid [^99mTc(V)DMSA]. Biodistribution was studied in mice by frozen section whole-body autoradiography and microautoradiography in selected tissues. Binding to bone mineral analogues was studied in vitro using various forms of calcium phosphate and hydroxyapatite under varied conditions. Similar studies with^99mTc-hydroxymethylene diphosphonate (HDP) were also carried out for comparison. The in vivo stability of^99mTc(V)DMSA was monitored by high-performance liquid chromatographic analysis of blood and urine samples taken over 24 h from patients injected with the tracer. Whole-body autoradiography shows that^99mTc(V)DMSA has highest affinity for bone (cortical rather than medullary) in mice. Substantial uptake of the tracer was also observed in the kidney (cytoplasm of cortical renal tubular cells). No specific localisation was observed in the liver at either the microscopic or the macroscopic level. While^99mTc-HDP bound strongly to calcium phosphates under all conditions,^99mTc(V)DMSA binding was inhibited in the presence of phosphate and was stronger at pH 6.0 than at pH 7.4. In non-phosphate buffers, however, the binding of^99mTc(V)DMSA remained high across the pH range 4–7.4.^99mTc(V)DTVISA binds to calcium phosphates chemically unaltered, and no radioactive species other than the three isomers of^99mTc(V)DMSA were detected in blood or urine samples taken from patients up to 24 h after injection.^99mTc(V)DMSA is stable in vivo, and no conversion of the complex to other chemical species needs to be invoked to explain its uptake in bone metastases or soft tissue tumour. Bone affinity may be due to reversible binding of the unaltered complex to the mineral phase of bone.