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Di-n-butyltin dichloride (DBTC) and tricyclohexyltin chloride (TCHTC) inhibited the glutathione S-transferase activity of rat liver cytosolic supernatants towards 1-chloro-2,4-dinitrobenzene. Meso-2,3-dimercaptosuccinic acid increased inhibition of glutathione S-transferase by DBTC but lowered inhibition of the enzyme by TCHTC.
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.
This preliminary study examined reno-vascular injury sustained by the multipapillary porcine kidney in acute and chronic complete ureteric obstruction. In combination with measurement of upper tract pressure, regional function was assessed by [99mTc]-dimercaptosuccinic acid (DMSA) uptake and qualitative renal perfusion, by resin casting of the arterial tree prior to scanning electron microscopy (SEM). In acute obstruction, segmental defects were noted in the renal poles on both [99mTc]-DMSA scanning and casting. On SEM there was a polar afferent arteriolar vasodilatation after 30 min of obstruction and, subsequently, a segmental reduction in cortical perfusion. In kidneys that had been obstructed for 20 days, we observed a marked reduction in outer cortical perfusion coincident with afferent arteriolar vasoconstriction. The pathogenesis and significance of segmental injury to the multipapillary kidney in obstructive uropathy is discussed.
Orally administered meso-2,3-dimercaptosuccinic acid (DMSA) is an effective antagonist for acute oral cadmium chloride (1 mmol/kg) intoxication in mice when administered up to 8 h after cadmium ingestion. Administration of sodium N-benzyl-N-dithiocarboxy-D-glucamine (NaB) i.p. along with DMSA p.o. resulted in kidney and liver cadmium levels only marginally smaller than those obtained with DMSA alone. Both chelation treatment regimens permitted survival of 80% or more of the animals, in comparison to a survival rate of 40-50% in untreated animals. Intraperitoneally administered NaB by itself is a very effective antagonist for cadmium chloride administered intraperitoneally in either acute or chronic cadmium intoxication. A dose-response study was made of the mobilization of cadmium from the liver and kidney of cadmium-loaded mice by NaB; this showed that NaB is one of the most effective cadmium mobilizing agents developed to date. We have also confirmed the earlier report of Kojima and his co-workers of the ability of NaB to remove cadmium from animals which have been treated with cadmium over an extended period of time. NaB causes a very large increase in the biliary excretion of cadmium. Nuclear magnetic resonance (NMR) spectra of 113Cd in bile from treated animals and model solutions indicates that such cadmium is undergoing rapid ligand exchange.
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.
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The clearance of 125I-sodium iothalamate, 131I-sodium hippurate, 99mTc-DMSA, and beta 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 (less than 14%). A similar difference between the two groups was found in the relative beta 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.
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are progressive neurodegenerative disorders involving motor neurones. The aetiology of the non-familiar forms is still unknown but it has been suggested that long-term exposure to heavy metals such as lead and mercury may play a role in the pathogenesis of these diseases. In 53 patients suffering from ALS (n = 42) and SMA (n = 9) the oral administration of dimercaptosuccinic acid (DMSA, 20 mg/kg) did not result in a greater mobilization of lead and mercury from peripheral depots than in control subjects. Although it cannot be excluded that the amount of lead or mercury excreted after DMSA administration may not be a reflection of the amount accumulated in the motor neurons, this study does not provide support for the hypothesis that heavy metals play a significant role in the occurrence of motor neurone diseases.
The aim of this work is to correlate the net kidney uptake of 99mTc-aprotinin (TcA) in 103 subjects with separate effective renal plasma flow (ERPF) and some blood chemistry parameters at 90, 180, and 360 min postinjection both in the normal and diseased kidney. Correlations found with separate ERPFs are highly significant at any time (P less than 0.001). However, although the slope of the regression line is steeper at 180 min, r tends to deteriorate slightly with time postinjection and a higher intercept on the y axis; this pattern is more pronounced if diseased kidneys are considered separately. The following are probably related to the renal handling of TcA: Early scans better reflect blood flow to the kidney, while later scans are more related to the metabolism/excretion tubular mechanisms; correlations found with urea, creatinine, urea clearance, and creatinine clearance are highly significant at any time; in 20 additional patients with diseased kidneys, renal uptake measurements done 360 min postinjection first with TcA and then with DMSA showed better correlations with ERPF employing TcA. Our results indicate that TcA is a feasible indicator of split renal function even at 90 min postinjection when a scan is easily carried out on an outpatient basis.
Aprotinin (Ap), a low-molecular-weight polypeptide (6500 dalton), is a protease inhibitor which is electively and stably accumulated in the kidney. In 112 adult patients, with either uni- or bilateral renal disease with different degrees of renal impairment (from normal GFR to advanced renal failure), renal scans were performed by means of Ap labelled with 99mTc. Highly satisfactory renal scans were obtained in all patients. In 20 patients with renal failure (serum creatinine 1.8-8.5 mg/dl, mean 4.7) a comparison was made of the renal scans obtained with 99mTc-Ap and with 99mTc-DMSA. 99mTc-Ap was slightly better than 99mTc-DMSA, especially in patients with far advanced renal failure. Some aspects of the pharmacokinetics of 99mTc-Ap were studied in 72 cases. In 22 of these patients plasma clearance of 99mTc-Ap was determined by the single injection method using a two-compartment model. In patients with GFR greater than 90 ml/min plasma clearance of 99mTc-Ap was 67.6 +/- 8.4 SD ml/min. A good correlation was observed between plasma clearance of 99mTc-Ap and GFR (r = 0.74). After IV injection 99mTc-Ap was stably fixed by the kidney. Renal radioactivity remained stable between the second and eighth hour after the injection. Urinary excretion of radioactivity measured in 35 patients in the first and in the second 2-h interval after IV injection of 99mTc-Ap was negligible in all patients (2.7 +/- 1.5 SD percent of the dose in the first 2 h; 2.8 +/- 1.4 SD between the second and fourth hour). 99mTc-Ap is an excellent agent for renal imaging. It also seems promising for renal function studies.
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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.
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Renal damage without scarring is a rare manifestation of reflux nephropathy, and is infrequently reported in the literature. A retrospective review of a large series of patients with urinary tract disorders at the hospital for Sick Children, Great Ormond Street, identified 12 patients with vesico-ureteric reflux (VUR) with no evidence of scarring but with renal damage as assessed using technetium 99m dimercaptosuccinic acid (99mTc-DMSA) scan. There were 9 simplex kidneys, the differential function was between 33% and 43% (mean 38%). On follow-up to date (mean 6.7 years) all kidneys show stable differential function with neither improvement nor deterioration. Only 8 children had a urinary tract infection. Renal damage without evidence of a focal scar associated with VUR may be a manifestation of growth arrest possibly due to glomerular damage. The sensitivity of 99mTc-DMSA may reveal the permanent nature of the renal damage.
This study was designed to evaluate the occurrence and the type of proteinuria in 82 children with vesico-ureteric reflux (VUR) with or without renal scars. The urinary excretion of the high molecular weight protein albumin was taken as an index of glomerular alterations and the excretion of retinol-binding protein (RBP), beta 2-microglobulin and brush border antigens (BBA) (measured by monoclonal antibody-based enzyme-linked immunosorbent assay) was taken as an index of tubular alterations. All such markers were increased in children with VUR and were related to the degree of renal function. Patients showing reduced creatinine clearance had very high levels of albuminuria, microproteinuria and BBA, with all these variables reciprocally correlated. In children with normal renal function however, only microproteins (not albumin or BBA) were slightly increased, thus indicating an isolated tubular defect without involvement of the proximal segment of the tubule. However, microprotein excretion did not correlate with the grade of scarring (99mtechnetium-dimercaptosuccinic acid scan), both RBP and beta 2-microglobulin excretion being normal in 75% of children with radioisotopic signs of renal lesions but increased in 17% of children without scars. Therefore, tubular proteinuria identifies different groups of children with VUR but is not related to renal scarring. Prospective studies will define the usefulness of proteinuria as a reliable indicator of renal outcome.
Neonatal renal venous thrombosis (NRVT) is a serious complication of newborns. Ultrasound is most useful in detecting NRVT. However, there is no detailed description of the evolution of ultrasound finding in NRVT. Here we report a patient with NRVT with complete ultrasound follow-up. Perivascular streaks were first seen at 3 days of age with a diffusely enlarged and echogenic right kidney. Echolucency then gradually appeared over the medulla area with shrinking renal size. Concomitant loss of renal function was evidenced by dimercaptosuccinic acid scan. The kidney became contracted at the age of 1 year. Since the pathognomonic perivascular streaks were present for only a few days, early ultrasound scanning should be performed for every newborn suspected of having NRVT.
Following the diagnosis of primary vesicoureteric reflux, identified as part of the investigation of urinary tract infection, 299 refluxing kidneys in 202 children (aged 0-14 years) were prospectively evaluated using intravenous urography (IVU) and the DMSA renal scan at least 4 weeks after urine infection. There was 88% concordance between IVU and the DMSA scan, but in 12% there were discrepancies manifested in 37 kidneys from 31 children. Thirty-four kidneys were normal on IVU but showed scars of reflux nephropathy (RN) on the technetium 99m--dimercaptosuccinic acid (DMSA) renal scan; 4 of these (2 infants and 2 pre-school children) had severe generalized changes on scanning. Three kidneys were normal of DMSA scan and, although abnormal on initial IVU, were considered to be normal when this was repeated. During a follow-up period of 5 years an annual DMSA was undertaken in 194 patients and the renal scars remained unchanged in all except 1 child. The IVU was repeated 1-3 years after the initial study in 31 children in which the results of the first imaging did not agree. In 28 patients (34 kidneys) in which the initial IVU was normal but the DMSA abnormal, IVU evidence of scarring emerged in 30 of 34 kidneys, including the 4 patients with severe generalized damage on the DMSA. We conclude that abnormalities detected by the DMSA scan may precede the radiological findings, especially in young children. Even severe RN can be established in kidneys that appear normal on the IVU.