Role of 2,3-dimercaptosuccinic acid in the treatment of heavy metal poisoning.
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Arsenic Poisoning↗
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2,3-Dimercaptosuccinic acid treatment of heavy metal poisoning in humans.
14 patients with heavy metal poisoning received 2,3-dimercaptosuccinic acid (DMSA). 12 subjects were given 30 mg/kg/day for 5 days; 1 subject was started on a lower dose because of a history of atopy; another subject was treated for 15 days because of very high initial blood lead concentrations. In the 9 subjects who had lead poisoning, DMSA decreased blood lead concentrations by 35 to 81%, and induced a 4.5- to 16.9-fold increase in mean daily urinary excretion of the metal. In the acutely arsenic-poisoned case, the plasma arsenic concentration on day 7 was half the pretreatment value, while no clear decrease was observed in a chronically exposed subject. In 3 mercury cases, DMSA increased daily mercury urinary excretion 1.5-, 2.8- and 8.4-fold, respectively, while blood mercury concentrations remained below detection limits. No serious side effects were observed and 3 weeks after administration of the drug the clinical condition of all subjects was either stable or improved. These results indicate the efficacy of DMSA for lead poisoning in humans and provide a rationale for further investigating its usefulness in mercury and arsenic poisoning cases.
Adolescent↗
Developmental effects of methylated arsenic metabolites in mice.
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Abnormalities, Drug-Induced↗
Lipoic acid in combination with a chelator ameliorates lead-induced peroxidative damages in rat kidney.
The deleterious effect of lead has been attributed to lead-induced oxidative stress with the consequence of lipid peroxidation. The present study was designed to investigate the combined effect of DL-alpha-lipoic acid (LA) and meso-2,3-dimercaptosuccinic acid (DMSA) on lead-induced peroxidative damages in rat kidney. The increase in peroxidated lipids in lead-poisoned rats was accompanied by alterations in antioxidant defence systems. Lead acetate (Pb, 0.2%) was administered in drinking water for 5 weeks to induce lead toxicity. LA (25 mg/kg body weight per day i.p.) and DMSA (20 mg/kg body weight per day i.p.) were administered individually and also in combination during the sixth week. Nephrotoxic damage was evident from decreases in the activities of gamma-glutamyl transferase and N-acetyl beta- D-glucosaminidase, which were reversed upon combined treatment with LA and DMSA. Rats subjected to lead intoxication showed a decline in the thiol capacity of the cell, accompanied by high malondialdehyde levels along with lowered activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione metabolizing enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase, glutathione- S-transferase). Supplementation with LA as a sole agent showed considerable changes over oxidative stress parameters. The study has highlighted the combined effect of both drugs as being more effective in reversing oxidative damage by bringing about an improvement in the reductive status of the cell.
Acetylglucosaminidase↗
Effect of various antidotes on the biliary and intestinal excretion of arsenic in situ and into the feces in vivo in guinea-pigs after injection of As2O3.
The effect of various antidotes on the excretion of arsenic into the feces in vivo and on the biliary and enteric excretion in situ was investigated on segments of jejunum and colon in anesthetized guinea-pigs using the pendular perfusion technique, according to Henning and Forth (1982). In the in situ experiments guinea-pigs received As2O3 (0.02 mmol As(III)/kg) and 30 min later, British-Anti-Lewisite (BAL), dimercaptopropanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA) or 2,3-bis-(acetylthio)propanesulfonamide (BAPSA) (0.1 or 0.7 mmol/kg each) into the jugular vein. In the in vivo experiments guinea-pigs received As2O3 s.c. (same dose as above) and 30 min later the same antidotes (0.1 mmol/kg i.p.). The feces were collected for 24 h and the arsenic content measured. During the 60-min perfusion period the amount of arsenic excreted into the jejunum or colon was only 3% or 0.4% of the dose administered, respectively. Of the arsenic dose, 8% was found in the bile. None of the antidotes had an effect on the arsenic excretion into the jejunum or colon. No change in biliary excretion was found in animals treated with BAL, 0.1 or 0.7 mmol/kg, respectively. DMSA, BAPSA or DMPS, 0.1 mmol/kg, increased the biliary excretion of arsenic to 14, 33, or 43% of the dose administered and after 0.7 mmol/kg to 29, 37, or 42%, respectively. Furthermore, a significant increase (P > 0.05) was found for the bile/blood concentration ratio in the following order: control < BAL < DMSA < BAPSA approximately DMPS.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Analysis of meso-2,3-dimercaptosuccinic acid in human urine by capillary electrophoresis using direct injection.
meso-2,3-Dimercaptosuccinic acid ( meso-DMSA) is an effective chelating agent for the treatment of lead poisoning. We have developed a capillary electrophoresis (CE) method to monitor the urinary excretion of meso-DMSA in human beings. The urine sample was directly injected for analysis in CE without the requirement of solid-phase extraction (SPE). The meso-DMSA was detected in 20 mM borate buffer (pH 8.3) using a 60-cm length bare fused-silica capillary (75-microm ID, 52.5-cm effective length). The meso-DMSA can be extensively biotransformed during metabolism, and no meso-DMSA in urine samples was found in our studies. Any metabolized meso-DMSA can be successfully converted to free meso-DMSA by chemical reduction with dithiothreitol (DTT). In addition, samples were also treated with ethylenediaminetetraacetic acid (EDTA) to transchelate any meso-DMSA that is coordinated with metal ions present in the urine samples. The total amount of meso-DMSA present as these chemical forms was quantified after chemical reduction and addition of EDTA. The detection limit of meso-DMSA was about 50 microM, the RSD of peak area and migration time of meso-DMSA were 4-8% and less than 1%, respectively.
Chelating Agents↗
Imaging of pyelonephritis.
OBJECTIVE: Accurate diagnosis of pyelonephritis using clinical and laboratory parameters is often difficult, especially in children. The main aims of this prospective study were to compare the value of different imaging techniques [renal sonography, cortical scintigraphy with technetium-99m dimercaptosuccinic acid (99mTc DMSA) and computed tomography (CT)] in detecting renal involvement in acute urinary tract infections and to determine the sensitivity of DMSA scans for permanent renal scars 6 months later. MATERIALS AND METHODS: Between February 1992 and January 1993, 55 children admitted to our pediatric unit with febrile symptomatic urinary tract infections were eligible for analysis. Ultrasonography (US), DMSA scanning and micturating cystourethrography were performed in every case. Only 18 children underwent CT. A second DMSA scan was performed in 48 children a mean of 7.5 months after the first. RESULTS: US abnormalities were found in 25 children (45 %). The first DMSA scan showed a parenchymal aspect suggestive of pyelonephritis in 51 patients (93 %). Among the 18 patients studied by CT, 14 had abnormalities. Normal US findings did not rule out renal parenchymal involvement. Scintigraphy appeared to be more sensitive than CT for renal involvement. The frequency and degree of initial renal parenchymal damage seemed to correlate with vesicoureteral reflux, but the most severe initial parenchymal defects were not associated with marked clinical or laboratory manifestations. Repeat DMSA scans, performed on 45 kidneys with abnormalities at the first examination, showed resolution in 19, improvement in 16, persistence in 8 and deterioration in 2. The prevalence of vesicoureteral reflux was not higher in patients with renal scarring on the second DMSA scan than in patients whose scans showed an improvement. CONCLUSION: DMSA scans should be considered as a reference in the detection and follow-up of renal scarring associated with acute urinary tract infection as this technique is more sensitive than US and CT, the latter being unsuitable because it entails radiation exposure and sedation of patients.
Acute Disease↗
Pentavalent rhenium-188 dimercaptosuccinic acid for targeted radiotherapy: synthesis and preliminary animal and human studies.
Pentavalent rhenium-188 dimercaptosuccinic acid [188Re(V)DMSA] is a beta-emitting analogue of 99mTc(V)DMSA, a tracer that is taken up in a variety of tumours and bone metastases. The aim of this study was to develop the kit-based synthesis of the agent on a therapeutic scale, to assess its stability in vivo, and to obtain preliminary biodistribution and dosimetry estimates, prior to evaluation of its potential as a targeted radiotherapy agent. The organ distribution of 188Re in mice was determined 2 h after injection of 3 MBq 188Re(V)DMSA prepared from eluate from a 188W/188Re generator. Three patients with cancer of the prostate and three with cancer of the bronchus, all with bone metastases confirmed with a standard 99mTc-hydroxymethylene diphosphonate (99mTc-HDP) scan, were given 370 MBq 188Re(V)DMSA and imaged at 3 h and 24 h using the 155-keV gamma-photon (15%). Blood and urine samples were collected to determine clearance and to analyse the speciation of 188Re. Organ residence times were estimated from the scans, and used to estimate radiation doses using MIRDOSE 3. In mice, 188Re(V)DMSA was selective for bone and kidney. In patients, it showed selectivity for bone metastases (particularly those from prostate carcinoma) and kidney, but uptake in normal bone was not significantly greater than in surrounding soft tissues. Of the normal tissues the kidneys received the highest radiation dose (0.5-1.3 mGy/MBq). The images were strongly reminiscent of 99mTc(V)DMSA scans in similar patients. High-performance liquid chromatography analysis of blood and urine showed no evidence of 188Re in any chemical form other than 188Re(V)DMSA up to 24 h. In conclusion, 188Re(V)DMSA and its 186Re analogue warrant further clinical assessment as generator/kit-derived agents for treatment of painful bone metastases. These agents should also be assessed in medullary thyroid carcinoma and other soft tissue tumours which have been shown to accumulate 99mTc(V)DMSA.
Aged↗
Kidney length and scarring in children with urinary tract infection: importance of ultrasound scans.
BACKGROUND: Many studies have demonstrated that dimercaptosuccinic acid (DMSA) scintigraphy is the most sensitive diagnostic method in the identification of irreversible renal lesions (scars) in children with previous episodes of acute pyelonephritis (APN). This study assessed the reliability of ultrasound in identifying reflux nephropathy in children with acute pyelonephritis with or without vesicoureteric reflux (VUR). METHODS: Eighty children (45 female and 35 male, age range 5 months to 10 years, average age 2 years 1 month) with a positive history for at least one episode of APN participated in this study. All children underwent voiding cystourethrography, DMSA scintigraphy 4 to 8 months after the most recent episode of APN, and an ultrasound test evaluation less than 2 months after DMSA scintigraphy. RESULTS: Voiding cystourethrograms showed VUR in 52 children (68%); 13 of these were bilateral, for a total of 65 refluxing kidney units of the 154 (42%) evaluated; DMSA scintigram was normal for 108 of 154 kidneys (70%). Of the 65 kidneys with VUR, DMSA scintigram displayed normal findings in 29 cases (45%) and pathologic findings in 36 (55%). In the 79 nonrefluxing kidneys, DMSA scintigram was normal in 69 cases (87%). The relative risk of scarring in VUR kidneys is 2.6. The ultrasound study recorded a maximum longitudinal diameter between the 5th and 95th percentiles in 80 of 89 (81%) kidneys without VUR and in 21 of 65 (32%) with VUR. A significant correlation was found between maximum longitudinal diameters and DMSA scintigraphic findings in kidneys with VUR and those without VUR, respectively. CONCLUSION: This study establishes that ultrasound scans, by means of a simple and reproducible measurement technique, maximum longitudinal diameter, have a predictive value with regard to the presence of scars, with few exceptions. This finding, in our opinion, could lead to a decrease in the number of invasive procedures, in particular DMSA scan, in patients with APN.
Child↗
Lack of association of IL8 gene polymorphisms with familial vesico-ureteral reflux.
Vesico-ureteral reflux (VUR) is the most common inherited disorder of the lower urinary tract. Children with VUR are at risk for ongoing renal damage with subsequent infections. IL8 is an important inflammatory mediator which can be produced by epithelial cells of the renal tract in response to a variety of inflammatory stimuli. High serum concentrations of IL-8 have been reported in patients with chronic renal failure. Elevated IL-8 levels have been reported in the urine of patients with VUR and renal parenchymal scarring (RPS). More recently it was reported that urine IL-8 levels remain elevated in infants with VUR even in the absence of a urinary tract infection (UTI). Increased IL-8 expression has been shown to be associated with polymorphism at position -251 (rs4073) of the IL-8 promoter. The aim of this study was to examine the association of IL-8 gene polymorphism with familial VUR in a cohort of 219 siblings from 109 families affected with VUR, the largest such cohort tested to date. RPS was assessed using dimercaptosuccinic acid scintigraphy. Genotyping was performed in 219 siblings with VUR (157 without RPS, 62 with RPS) and 292 controls for the position -251 of IL-8 gene by polymerase chain reaction with tetra primers and gel analysis. Genotype was compared using the chi square test. Statistical significance was taken as a value of P < 0.05. There were no significant differences in IL-8 -251 genotype frequency between VUR patients and controls. Similarly, gender, severity of VUR and renal parenchymal scarring had no effect on IL-8 -251 genotype frequency. Although IL-8 urinary levels have been reported to be elevated in VUR, our data indicate that IL-8 gene is not involved in the pathogenesis of familial VUR or reflux nephropathy.
Chelating Agents↗
The role of DMSA scans in evaluation of the correlation between urinary tract infection, vesicoureteric reflux, and renal scarring.
The correlation between urinary tract infection (UTI), vesicoureteric reflux (VUR) and renal scarring was studied in 89 patients (177 renal units; 1 solitary kidney) during the period 1997-2000. There were 63 males and 26 females; ages ranged from neonates to 14 years. UTI was diagnosed on the basis of a positive urine culture, VUR was diagnosed and graded by micturating cystourethrogram (MCU), and renal scarring was assessed by technetium 99 m Tc-dimercaptosuccinic acid (DMSA) scan. Ultrasonography (US) was done to evaluate renal tract dilatation and other structural abnormalities. A follow up DMSA scan was performed approximately 6 months after the initial scan. VUR was present in 106 of the 171 renal units in which it was studied and absent in 65 units. The majority of the VUR was grade V. Renal scars were seen in 90 of 177 renal units at presentation and in 72 of the 163 renal units studied at follow-up. Some information was lacking in 31 patients; hence, the correlation between UTI, VUR, and renal scarring was done in 58 patients. The majority of the suspected scars at presentation were not seen at follow-up, but most of the established scars persisted. Only 2 renal units showed scars for the first time on follow-up. On US, approximately 50% of normal kidneys showed either suspicious or established scars on DMSA scan, and patients with bilateral abnormality on US showed renal scars. Renal scars were seen in 15 of 23 children without VUR, 17 of 18 with unilateral VUR, and 16 of 17 with bilateral VUR. Thus, there is a cause-and-effect relationship between UTI and renal scarring that is made worse by VUR. DMSA scans have been shown to be the most reliable method of assessing renal scarring, and an abnormal US scan showing upper-tract dilatation or a structural abnormality may have a predictive value in the detection of renal scarring.
Adolescent↗
Lead poisoning from souvenir earthenware.
A case of massive lead poisoning from juice contained in a Greek earthenware jug as well as six satellite cases of high lead exposure of similar origin is reported. The intoxicated patient was successfully treated with dimercaptosuccinic acid. Ceramic producers should adhere to the longstanding European legislation.
Adult↗
A comparison of different lead biomarkers in their associations with lead-related symptoms.
OBJECTIVES: To evaluate whether dimercaptosuccinic acid (DMSA) -chelatable lead, an estimate of current bioavailable lead stores, is a better predictor of lead-related symptoms than are other commonly used lead biomarkers. METHODS: A total of 95 male lead workers from three lead industries (one secondary lead smelting facility, one polyvinyl chloridestabilizer manufacturing plant, and one lead-acid storage battery factory), and 13 workers without occupational lead exposure recruited from an occupational health institute, were studied. Blood lead, blood zinc protoporphyrin (ZPP), 4 h DMSA-chelatable lead (after oral administration of 10 mg/kg DMSA), urine lead, and urinary delta-aminolevulinic acid levels were evaluated as predictors of 15 lead-related symptoms, assessed by self-administered questionnaire, with linear and logistic regression controlling for covariates. Total symptoms and symptoms in three categories (gastrointestinal, neuromuscular, and general) were evaluated. RESULTS: The mean (SD) 4 h DMSA-chelatable lead level was 288.7 (167.7) microg, with a range from 32.4 to 789 microg in the 95 lead workers. The mean (SD) in the non-exposed subjects was 23.7 (11.5) microg with a range from 10.5 to 43.5 microg. Blood lead, blood ZPP, and spot urine lead levels ranged from 21.4 to 78.4 microg/dl, 40 to 331 microg/l, and 7.5 to 153.0 micro/l, respectively, in the lead workers, and from 4.0 to 7.2 micro/dl, 27 to 52 microg/l, and 2.9 to 15.5 microg/l in the non-exposed controls, respectively. The overall mean symptom score (SD), derived as the sum of 0 or 1 point for absence or presence of 15 symptoms, of the lead workers was 3.7 (2.0), compared to 1.2 (1.5) for the non-exposed workers. DMSA-chelatable lead was the best predictor of symptom scores in both crude and adjusted analyses, compared with the other biomarkers. Lead workers with DMSA-chelatable lead values greater than the median (260.5 microg) were 6.2 times more likely to have frequent tingling or numbness of the arms or legs and 3.3 times more likely to have muscle pain than subjects with lower chelatable lead values. Three symptoms (tingling or numbness of arm or leg, muscle pain, and feeling irritation at the slightest disturbance) evidenced a dose-dependent relationship with DMSA-chelatable lead levels. CONCLUSIONS: DMSA-chelatable lead was found to be the best predictor of lead-related symptoms, particularly of both total symptom scores and neuromuscular symptoms, than were the other other lead biomarkers.
Adult↗
Five-year study of medical or surgical treatment in children with severe vesico-ureteral reflux dimercaptosuccinic acid findings. International Reflux Study Group in Europe.
UNLABELLED: The results of serial dimercaptosuccinic acid (DMSA) imaging over 5 years are reported in 287 children with severe vesico-ureteral reflux entered into the European Branch of the International Reflux Study in Children. The children were randomly allocated to medical (n=147) or surgical (n=140) management and DMSA studies were performed during the follow up period at least 6 months after any urinary tract infection. Abnormal images were classified into four types: (1) large polar hypodensity with normal renal outline; (2) peripheral photon deficient defect(s) in a non-deformed kidney; (3) small renal image with normal contour; and (4) peripheral defect(s) with resultant irregularity of the renal outline. The DMSA findings were abnormal at entry in 235 (82%) with no difference in incidence or severity between the two treatment groups. During follow up, deterioration was observed in 25 medically and 23 surgically treated patients and comprised image deterioration alone in 17, image deterioration with corresponding reduction in differential function in 16 and reduction in relative function without image change in 15, with similar distribution between the two treatment groups. Deterioration was more frequent in children entering the study under the age of 2 years and in those with grade IV rather than grade III reflux. These findings, showing no difference in outcome between children managed surgically or medically, are consistent with the radiological results already published. CONCLUSION: In the International Reflux Study the DMSA scintigraphic data showed no difference in outcome between children managed surgically or medically.
Child↗
Procalcitonin as a marker of acute pyelonephritis in infants and children.
In the absence of specific symptomatology in children, the early diagnosis of acute pyelonephritis is a challenge, particularly during infancy. In an attempt to differentiate acute pyelonephritis from lower urinary tract infection (UTI), we measured serum procalcitonin (PCT) levels and compared these with other commonly used inflammatory markers. We evaluated the ability of serum PCT levels to predict renal involvement, as assessed by dimercaptosuccinic acid (DMSA) scintigraphy. Serum C-reactive protein (CRP), leukocyte counts, and PCT levels were measured in 64 children admitted for suspected UTI. Renal parenchymal involvement was assessed by (99m)Tc-DMSA scintigraphy in the first 7 days after admission. In acute pyelonephritis, the median PCT level was significantly higher than in the lower UTI group (3.41, range 0.36-12.4 microg/l vs. 0.13, range 0.02-2.15 microg/l, P<0.0001). In these two groups, respectively, median CRP levels were 120 (range 62-249 mg/l) and 74.5 (range 14.5-235 mg/l, P=0.012) and leukocyte counts were 15,910/mm(3) (range 10,200-26,900) and 14,600/mm(3) (range 8,190-26,470, P=0.34). For the prediction of acute pyelonephritis, the sensitivity and specificity of PCT were 94.1% and 89.7%, respectively; CRP had a sensitivity of 100%, but a specificity of 18.5%. We conclude that serum PCT may be an accurate marker for early diagnosis of acute pyelonephritis.
Acute Disease↗
Reflux nephropathy in transplants.
Reflux nephropathy, renal scarring after urine infection, typically occurs in infancy. Although vesicoureteric reflux occurs commonly in kidney allografts, grafts have not previously been regarded as likely to be affected by reflux nephropathy, perhaps because older kidneys are considered to have matured out of the risk. Evidence that adult pigs remain at risk of reflux nephropathy challenges that assumption. We therefore reviewed the pathological findings in allograft nephrectomy specimens to look for evidence of reflux nephropathy, and sought evidence of focal transplant renal scarring in paediatric recipients who had a urine infection and vesicoureteric reflux. Consecutive allograft nephrectomy specimens (146) that had been removed between 1990 and 1999 were examined for evidence of reflux nephropathy, and relevant case notes were reviewed. Also, children with a renal transplant who had a urine infection were investigated for focal scarring by dimercaptosuccinic acid (DMSA) scanning and for reflux with a cystogram. Four transplanted kidneys from adult donors that were removed from adult recipients had developed changes consistent with reflux nephropathy. Of these, 3 also had definite evidence and 1 probable evidence of a glomerulopathy associated with hyperfiltration due to reduced renal mass. All 4 patients had had recurrent urine infection and the 2 assessed had had vesicoureteric reflux. Two children with renal transplants that also had urine infections and vesicoureteric reflux to their graft were shown to have sustained focal damage on DMSA scan, confirmed as reflux nephropathy scarring on biopsy in 1 case. The grafts were aged 14.4 years and over 16 years at the time of scarring. Reflux nephropathy can occur in previously healthy adult human kidneys after transplantation. Previous studies of the effect of vesicoureteric reflux on renal allografts were not designed to assess the possibility of mild or focal scarring.
Adolescent↗
Acute renal damage in infants after first urinary tract infection.
Urinary tract infection (UTI) is one of the most common causes of unexplained fever in neonates. The aim of this study was to determine the incidence of urinary tract anomalies and acute renal damage in neonates who presented with first urinary tract infection in the first 8 weeks of life. We reviewed the records of 95 infants, who were hospitalised with UTI during a 6-year period (1994-1999). Patients with antenatally diagnosed hydronephrosis and incomplete radiological investigations were excluded from the study. Of the remaining 57 patients, 42 were boys and 15 girls. The mean age at diagnosis was 32 days (range 5-60 days). All patients underwent renal ultrasonography (US), voiding cystourethrogram (VCUG) and (99m)Tc-dimercaptosuccinic acid (DMSA) scan. Urinary tract abnormalities were detected in 20 (35%) patients. Vesicoureteral reflux (VUR) was found in 19 (33%) neonates, 7 girls and 12 boys. Acute cortical defects on DMSA scan were present in 19 kidneys of patients with VUR and in 25 of those without reflux. Only one-third of neonates after first symptomatic UTI had VUR. We recommend that US, VCUG, and DMSA scan should be routinely performed after the first UTI in infants younger than 8 weeks.
Acute Disease↗
Acute pyelonephritis and sequelae of renal scar in pediatric first febrile urinary tract infection.
To investigate the incidence of acute pyelonephritis (APN) and renal scarring in children with febrile urinary tract infection (UTI), 191 of 216 (88%) children with their first episode of UTI received (99m)Tc-dimercaptosuccinic acid renal single-photon emission computed tomography. They were investigated within 7 days of admission and were followed for 6 months. One hundred and six patients (49.1%) underwent a voiding cystourethrogram. The incidence of vesicoureteric reflux (VUR) in group I (</=1 year old) was 22%, group II (1-5 years old) 69%, and group III (5-17 years old) 44%. The overall incidence of APN in febrile UTI was 70% (male 66%, female 76%, P=0.110). Children had a higher incidence of APN than infants ( P<0.05 in group I vs. II and group I vs. III). Of patients with APN, 57% (35/61) showed renal scar formation. VUR was found in 31%(24/78) of children with APN and 58% (14/24) of children with renal scar. In addition, children with high-grade VUR were more susceptible to APN and scar formation than those with low-grade VUR ( P<0.05). Older children with a first febrile UTI had a higher incidence of APN than infants (</=1 year), and half of the children with APN developed a renal scar.
Acute Disease↗