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PubMed1992

Experimental model of lead nephropathy. II. Effect of removal from lead exposure and chelation treatment with dimercaptosuccinic acid (DMSA).

Male Sprague-Dawley rats were exposed to high-dose (0.5%) lead acetate for periods ranging from 1 to 9 months; then lead exposure was discontinued, and animals were sacrificed after 12 months. Controls were pair-fed. Two additional groups of low-dose (0.01%) and high-dose (0.5%) rats were exposed to lead for 6 months, then lead was discontinued and the rats were treated with three 5-day courses of 0.5% DMSA (dimercaptosuccinic acid) over the next 6 months. Controls were rats exposed to lead for 6 months, then removed from exposure for 6 months without receiving DMSA. Low-dose lead-treated rats showed no significant pathological changes with or without DMSA treatment, but exhibited a significant increase in GFR after DMSA. High-dose lead-treated animals showed no functional or pathological changes when lead exposure was discontinued after 1 month. However, when duration of exposure was 6 or 9 months, GFR was decreased and serum creatinine and urea nitrogen were increased as compared to controls. Tubulointerstitial disease was severe. Administration of DMSA resulted in an improvement in GFR and a decrease in albuminuria, together with a reduction in size and number of nuclear inclusion bodies in proximal tubules. However, tubulointerstitial scarring was only minimally reduced. It may be concluded that, except for brief initial exposure, discontinuation of high-dose lead exposure fails to reverse lead-induced renal damage. Treatment with the chelator, DMSA, improves renal function but has less effect on pathological alterations. As GFR improved after DMSA treatment in both low-dose and high-dose lead-treated rats, irrespective of the degree of pathological alterations, it may be concluded that the DMSA effect is most likely mediated by hemodynamic changes.

Acetylglucosaminidase↗
PubMed1987

Methylmercury chloride-induced and antagonist-reverted succinic dehydrogenase changes in the brain and trigeminal ganglia of the rat.

The effect of methylmercury chloride (MMC) toxicity and its antagonism by chelating agents (N-acetyl-DL-homocysteine thiolactone and 2,3-dimercaptosuccinic acid) on succinic dehydrogenase (SDH) activity of fore-, mid-, and hindbrain and trigeminal ganglia of rats is reported in this study. A dose of 10 mg MMC/kg body weight was injected subcutaneously for 2, 7, and 15 days. The chelating agents were also injected subcutaneously in two separate groups of MMC-treated animals except in group 3. In the latter case MMC was injected in two groups of rats for 7 days, and thereafter antagonists were administered daily (40 mg/kg) for 1 week. The result shows inhibition of the enzyme with MMC in all groups and its restoration by N-acetyl-DL-homocysteine thiolactone; 2,3-dimercaptosuccinic acid, however, further reduced the enzyme level. The significance of inhibition of the enzyme in relation to tissue respiration and ATP production is discussed and the capacities of antagonists in the restoration of the SDH level are also analyzed.

Animals↗
PubMed2003

Metal chelators change the human sperm motility pattern.

OBJECTIVE: To investigate the influence of zinc on the generation of motility. DESIGN: Prospective study. SETTINGS: Outpatient clinic of the Center of Dermatology and Andrology. PATIENT(S): Seventy-three patients and 10 sperm donors. INTERVENTION(S): Motile spermatozoa were isolated by swim-up and incubated for 1, 2, 4 or 6 hours with DL-penicillamine, 2,3-dimercaptopropan-1-sulfonate, and meso-2,3-dimercapto-succinimic acid at concentrations of 1, 10, and 100 micro mol/L. MAIN OUTCOME MEASURE(S): Motility was analyzed by means of computer-assisted semen analysis (CASA). RESULT(S): Significant dose-dependent changes in nonlinear motility, progressive motility, and velocity straight line (VSL) were observed. After only 1 hour of incubation, nonlinear motility decreased, and progressive motility and VSL increased. The percentage of immotile spermatozoa was not affected. Time-dependent changes in motility were observed on a significantly higher or lower level as compared to the control. Comparing the chelators after 2 hours revealed that DL-penicillamine showed the strongest effect on the sperm. CONCLUSION(S): The results imply that chelators can eliminate at least some part of the zinc from the flagellum. This zinc elimination appears to lead to comparable changes of the outer dense fibers as seen in vivo during epididymal maturation, finally resulting in improved motility.

Chelating Agents↗
PubMed1999

Contralateral reflux after unilateral ureteral reimplantation--preexistent rather than new-onset reflux.

PURPOSE: The authors studied the preoperative Technetium 99m-dimercaptosuccinic acid renal scan (DMSA) of patients undergoing unilateral vesicoureteral antireflux surgery to compare the amount of renal scarring between the refluxing and the contralateral renal units. They sought to determine whether postoperative contralateral vesicoureteral reflux was preexistent or new onset. METHODS: Sixty-eight patients who underwent unilateral vesicoureteral antireflux surgery and had preoperative DMSA and postoperative voiding cystourethrography (VCUG) examinations were studied. Preoperative DMSA results were analyzed to determine the amount of renal scarring in each kidney. RESULTS: Sixty-four (94.1%) ipsilateral refluxing renal units had renal scars. Of the 68 contralateral renal units, scars were noted in 28 (41.2%). The rate of nonscar was 4 of 68 (5.9%) in reflux kidneys, which was significantly lower than 40 of 64 (62.5%, excluding 4 with a history of resolved reflux) in nonreflux kidneys (P<.001). Of 40 contralateral nonscarred kidneys, 1 of 40 (2.5%) had subsequent reflux, which was significantly lower than 5 of 28 (17.9%) of scarred kidneys (P<.005). Six patients (8.8%) had contralateral reflux, and 1 of them had a history of resolved reflux. Of the 6 contralateral kidneys with severe scarring involving 3 poles or contracted, 4 of 6 (66.7%) had subsequent reflux. CONCLUSIONS: Scar in the contralateral kidney seen on DMSA scan seems to predict contralateral reflux after unilateral antireflux surgery. The contralateral reflux may be preexistent. Postoperative VCUG should be performed routinely for patients who have contralateral renal scars. In patients with a history of contralateral reflux or severe contralateral renal scar, simultaneous contralateral ureteral reimplantation should be considered.

Adolescent↗
PubMed1992

Controlled study of meso-2,3-dimercaptosuccinic acid for the management of childhood lead intoxication.

We examined the efficacy and safety of meso-2,3-dimercaptosuccinic acid (DMSA) in children with markedly elevated blood lead (BPb) concentrations. Among 19 children with BPb concentrations of 50 to 69 micrograms/dl (2.41 to 3.33 mumol/L) who received a 5-day inpatient oral course of DMSA (1050 mg/m2 per day), the mean BPb concentration decreased by 61%; in four who received calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) (1000 mg/m2 per day intravenously), it decreased by 45% (p less than 0.0007). Urinary lead excretion was comparable in both groups. Treatment with DMSA was more effective than treatment with CaNa2EDTA in restoring metabolic activity to the heme pathway and was well tolerated even among nine patients who received concomitant iron supplementation and two who had homozygous deficiency of glucose-6-phosphate dehydrogenase. On discharge, these 19 children received either no chelation therapy or DMSA, 350 or 700 mg/m2 per day for 14 days on an outpatient basis. After 14 days the mean BPb values for the no-chelation, low-DMSA, and high-DMSA groups were 73%, 66%, and 50% of the pretreatment values, respectively. We conclude that a 5-day oral course of DMSA is effective in the treatment of children with severe lead poisoning. In addition, on an outpatient basis the administration of DMSA, 700 mg/m2 per day, is capable of delaying the typical rebound in BPb values and should ultimately reduce the need for repeated hospitalizations.

Administration, Oral↗
PubMed1992

Evaluation of renal scars by technetium-labeled dimercaptosuccinic acid scan, intravenous urography, and ultrasonography: a comparative study.

The objective of our prospective study was to compare the sensitivity and specificity of ultrasonography, intravenous pyelography, and dimercaptosuccinic acid scan in detecting scarred kidneys. Twenty-seven consecutive subjects with recurrent urinary tract infections, vesicoureteral reflux, scarred kidneys, or a combination of these problems had all three imaging procedures performed. With the total number of scars serving as the gold standard, the sensitivity (94%) and specificity (100%) in identifying renal scars in children were highest for the DMSA scan. Intraobserver (95%) and interobserver (90%) reliability were also high for the DMSA scan. However, the clinical interpretation of the increased sensitivity of the DMSA scan is unknown. Changes on the scan not identified by intravenous urography may not represent true scars. Research into the long-term significance of these scars is indicated.

Adolescent↗
PubMed1993

Silent renal damage in symptom-free siblings of children with vesicoureteral reflux: assessment with technetium Tc 99m dimercaptosuccinic acid scintigraphy.

Sixteen symptom-free siblings of children with vesicoureteral reflux were found to have the condition and underwent renal scintigraphy with technetium 99m dimercaptosuccinic acid. Of these 16 children, 6 had scintigraphic evidence of renal damage. Screening for vesicoureteral reflux in siblings of children known to have the condition should therefore be carried out early in life; when reflux is present, an immediate assessment of the renal parenchyma should be made.

Child↗
PubMed1988

Dose-response study of oral 2,3-dimercaptosuccinic acid in children with elevated blood lead concentrations.

2,3-Dimercaptosuccinic acid (DMSA) is an orally effective orphan drug that is more specific and has a wider therapeutic index than other currently available drugs used for lead intoxication. Its investigational use in the United States has been limited to the treatment of men with occupational plumbism. Twenty-one children with blood lead concentrations of 31 to 49 micrograms/dl, who also had a positive calcium disodium edetate (CaNa2EDTA) mobilization test result, were hospitalized for 7 days. Fifteen children were randomly assigned to three groups that received either 350, 700, or 1050 mg/m2/day, respectively, of DMSA in three divided doses daily. A fourth group of six children received conventional treatment with 1000 mg/m2/day of intravenously administered CaNa2EDTA in two divided doses daily. The 1050 mg/m2/day dose of DMSA was significantly more effective than lower doses of DMSA or intravenously administered CaNa2EDTA in reducing blood lead levels and restoring erythrocyte delta-aminolevulinic acid dehydratase activity. Intravenously administered CaNa2EDTA significantly increased the urinary excretion of several essential minerals (zinc, copper, iron, and calcium), whereas DMSA did not. The DMSA was well tolerated and appears extremely promising as a drug that will simplify the management of childhood lead poisoning.

Administration, Oral↗
PubMed1994

Pharmacokinetics of meso-2,3-dimercaptosuccinic acid in patients with lead poisoning and in healthy adults.

We compared the pharmacokinetics of meso-2,3-dimercaptosuccinic acid (DMSA) in three children with lead poisoning, three adults with lead poisoning, and five healthy adult volunteers. All subjects received DMSA orally. Maximum blood concentration and time to maximum blood concentration of total DMSA concentration were not statistically different among the groups. Unaltered DMSA was detected in the blood of all poisoned patients but in only one of five healthy volunteers. Elimination half-life of total DMSA (parent drug plus oxidized metabolites) was longer in children with lead poisoning (3.0 +/- 0.2 hours) than in adults with lead poisoning (1.9 +/- 0.4 hours) and healthy adults (2.0 +/- 0.2 hours). Renal clearance of total DMSA was greater in healthy adults (77.0 +/- 13.2 ml/min per square meter) than in either adults (24.7 +/- 3.3 ml/min per square meter) or children with lead poisoning (16.6 ml/min per square meter); renal clearance of the metabolites of DMSA was also greater in healthy adults (64.6 +/- 10.1 ml/min per square meter) than in either adults (35.4 +/- 8.4 ml/min per square meter) or children with lead poisoning (19.5 ml/min per square meter). The DMSA appeared to enter the erythrocytes of patients with lead poisoning to a greater extent than in healthy adults. We conclude that renal clearance of DMSA and its metabolites may be impaired and that the distribution of DMSA in children with lead poisoning may be different from that in adults.

Adult↗
PubMed1994

Cortical scintigraphy in the evaluation of renal parenchymal changes in children with pyelonephritis.

We designed a prospective study to evaluate the ability of dimercaptosuccinic acid cortical scintigraphy and ultrasonography to detect renal parenchymal lesions in children with pyelonephritis. One hundred eleven patients 1 week to 16 years of age (median 5.5 months) with a urine culture positive for pathogens were included in the study; cortical scintigraphy and ultrasonography were repeated in 25 children after a mean follow-up of 10.5 months. Cortical scintigraphy showed renal changes in 74 children (67%), and ultrasonography showed renal changes in 39 (35%) (p < 0.001); results of the two examinations were discordant in 49 patients (kappa = 0.19). Children more than 1 year of age had a higher incidence of renal lesions than did younger children (85% vs 66%; p = 0.04). The presence of inflammatory signs (erythrocyte sedimentation rate or C-reactive protein) had an 89% sensitivity and a 25% specificity in identifying renal lesions. Among children with renal changes, vesicoureteric reflux was present in 39%. At follow-up examination, 16 children (64%) had scars. Thus we found a high incidence of renal involvement in children with pyelonephritis. We found that cortical scintigraphy is more sensitive than ultrasonography in detecting renal changes, and we believe that it should be added to the initial examination of children with suspected pyelonephritis.

Adolescent↗
PubMed1994

Efficacy of oral meso-2,3-dimercaptosuccinic acid therapy for low-level childhood plumbism.

OBJECTIVE: To compare the response to oral meso-2,3-dimercaptosuccinic acid (DMSA) treatment in children with an initial blood lead (BPb) concentration less than versus more than 2.17 mumol/L (45 micrograms/dl). DESIGN: Retrospective cohort study. SETTING: Regional referral lead treatment program in an urban children's hospital. PATIENTS: Thirty consecutive children, median age 34 months (range, 5 to 161 months), with an initial BPb concentration 0.97 to 2.90 mumol/L (20 to 60 micrograms/dl) selected for DMSA use. Reasons for DMSA use included BPb concentration > 2.17 mumol/L (11 children), complications with penicillamine therapy (11), chronic renal failure (1), and compassionate use (7). All patients received required environmental hazard reductions before drug administration. RESULTS: Group 1 (n = 23) had a mean BPb concentration of 1.50 mumol/L (31 micrograms/dl), and group 2 (n = 7) had a mean BPb concentration of 2.41 (51 micrograms/dl). Sixteen patients (70%) in group 1 and five patients (71%) in group 2 had had previous chelation therapy (p value not significant). No significant difference was found in the mean percentage of the reduction of BPb concentration during treatment of group 1 (60%) versus group 2 (58%). The mean BPb concentration in group 1 rebounded to 70% of pretreatment values by mean day 41; the BPb concentration in group 2 rebounded to 69% by day 37 (p value not significant). Prior chelation therapy did not result in a significant difference in either the percentage reduction of BPb concentration or the percentage of rebound BPb. CONCLUSION: DMSA is equally effective in acutely lowering BPb concentration in children with BPb concentrations less than and greater than 2.17 mumol/L.

Adolescent↗
PubMed1995

Relationship of asymptomatic bacteriuria and renal scarring in children with neuropathic bladders who are practicing clean intermittent catheterization.

OBJECTIVE: To determine whether untreated asymptomatic bacteriuria is associated with renal scarring in children with neuropathic bladders managed with clean intermittent catheterization (CIC). DESIGN: Retrospective study of 207 patients aged 1 to 30 years (mean 11.9 +/- 5.5 years) treated with CIC for a mean duration of 6.6 +/- 3.9 years by the spina bifida program at Children's National Medical Center. All patients were examined for renal scarring with dimercaptosuccinic acid (DMSA) renal scans. Catheterized urine cultures were obtained annually, but bacteriuria ( > 10,000 colony-forming units of a single organism per milliliter) was treated only if the patients had symptoms or if vesicoureteral reflux (VUR) was present. RESULTS: Of 207 children, 176 (85%) had one or more episodes of untreated asymptomatic bacteriuria and 72 (35%) had one or more febrile episodes associated with positive urine culture results. Biannual DMSA scans detected 54 new scarring episodes in 42 patients. Of newly recognized scars, 55% were preceded within 1 year by a febrile infection, 26% were detected in patients with VUR and asymptomatic bacteriuria, and 19% were detected in new patients during their initial examination. Univariate analysis revealed that new scarring was present in 35 of 176 patients with asymptomatic bacteriuria compared with 7 of 31 patients without (p = 809). Logistic regression analysis revealed that factors associated with scarring were febrile infections (adjusted odds ratio [OR] = 30.6, 95% confidence interval [CI] = 9.8 to 95.8), age more than 20 years (OR = 4.3, CI = 1.01 to 18.5), the presence of bladder trabeculation (OR = 2.7, CI = 1.0 to 7.6), and VUR (OR = 58.8, CI = 6.3 to 547.3), but asymptomatic bacteriuria was not associated with scarring. CONCLUSION: In the absence of VUR, asymptomatic bacteriuria in patients undergoing CIC is not a significant risk factor for scarring and does not require antibiotic therapy.

Adult↗
PubMed1996

Renal damage one year after first urinary tract infection: role of dimercaptosuccinic acid scintigraphy.

OBJECTIVE: The aim of this study was to determine whether age, C-reactive protein (CRP), body temperature, or results of voiding cystourethrography at diagnosis of first-time symptomatic urinary tract infection could predict the risk of renal damage as evaluated by dimercaptosuccinic acid (DMSA) scintigraphy performed 1 year after the infection. DESIGN: The study included 157 children (median age, 0.4 year, range, 5 days to 5.8 years) with first-time symptomatic urinary tract infection. In children 1 year of age or older, a body temperature of 38.5 degrees C or higher was necessary for inclusion. CRP and body temperature were measured at the time of infection, and voiding cystourethrography was performed shortly thereafter. DMSA scintigraphy was performed 1 year later in all children. RESULTS: After 1 year, 59 (38%) of the 157 children had renal damage as evaluated by DMSA scintigraphy, and of these, 28 (47%) had reflux. There was a positive correlation between renal damage and CRP, body temperature, and reflux. Children with high levels of CRP, high fever, and dilating reflux had a risk of renal damage up to 10 times higher than children with normal or slightly elevated CRP levels, no or mild fever, and no reflux. CONCLUSION: CRP concentration and body temperature at the index infection, in combination with the results of voiding cystourethrography, are useful in classifying children at high and low risk of scintigraphic renal damage 1 year after urinary tract infection.

Age Factors↗
PubMed1997

Renovascular hypertension in children with moyamoya disease.

OBJECTIVES: To examine the incidence, clinical and radiologic findings, and response to treatment of renovascular hypertension (RVHT) in moyamoya disease (MMD). METHODS: A retrospective analysis of medical records in six RVHT cases (8.3%) among 72 MMD patients observed from November 1987 to December 1995. RESULTS: The age at onset of MMD ranged from 9 months to 7 years 1 month (mean, 3.3 years). The most common initial manifestation of MMD was transient ischemic attack. Hypertension was detected between 4 years 4 months and 12 years 3 months (mean, 7.87 years). Unstimulated plasma renin activity was elevated in all six cases. Renal ultrasonography and captopril technetium 99m-labeled dimercaptosuccinic acid scan showed abnormal findings in four of five and in three of four available studies, respectively. However, both imaging studies showed abnormal findings only in the most severely affected kidneys even with bilateral renal artery stenosis. Renal arteriography revealed bilateral lesions in three of the patients and unilateral lesions in the others. Renal angioplasty was performed in four cases but was successful in only one and partially successful in another. A renal artery specimen obtained during renal autotransplantation showed intimal fibroplasia. At the last follow-up, one patient had normal blood pressure without the use of antihypertensive agents, but the other five patients needed this medication to control blood pressure. CONCLUSION: Because RVHT may be more commonly associated with MMD than has hitherto been appreciated, it is recommended that blood pressure be carefully followed and that diagnostic procedures for RVHT be carried out in hypertensive patients with MMD.

Adolescent↗
PubMed1997

Comparison of dimercaptosuccinic acid and calcium disodium ethylenediaminetetraacetic acid versus dimercaptopropanol and ethylenediaminetetraacetic acid in children with lead poisoning.

OBJECTIVES: To compare the response to dimercaptopropanol (BAL) and calcium disodium ethylenediaminetetraacetic acid (EDTA) versus orally administered meso-2,3-dimercaptosuccinic acid (DMSA) and EDTA in children with lead poisoning. METHODS: Retrospective review of medical records of children admitted to MetroHealth Medical Center with a whole blood lead (BPb) concentration of 2.17 mumol/L (45 micrograms/dl) or more (or less than 2.17 mumol/L and not a candidate for outpatient oral chelation) and treated with BAL + EDTA or DMSA + EDTA. In each group, the mean BPb values at the end of therapy and at 14 and 33 days after chelation were compared with pretreatment BPb by the Wilcoxon signed-rank test, whereas the Mann-Whitney U test was used to compare percentage change from pretreatment at each follow-up day between the two groups. RESULTS: Twenty-three children received BAL + EDTA and 22 received DMSA + EDTA. The BPb values (mean +/- SD) at the end of therapy and at 14 and 33 days after chelation were significantly lower than pretreatment in both groups (BAL + EDTA: 17 +/- 10, 34 +/- 7, 36 +/- 11 vs 58 +/- 14 micrograms/dl, p < 0.02, 0.01, 0.001, respectively; DMSA + EDTA: 10 +/- 4, 30 +/- 10, 30 +/- 14 vs 50 +/- 10 micrograms/dl, p < 0.01, 0.001, 0.01, respectively). The percentage reduction (mean +/- SD) in BPb from pretreatment at the end of therapy and on days 14 and 33 after chelation did not differ between the groups (BAL + EDTA: -71.2% +/- 19.8%, -40.2% +/- 13.8%, -37.1% +/- 17%; DMSA + EDTA: -79.9% +/- 8.7%, -38.3% +/- 21.6%, -37% +/- 32%; p > 0.20). Elevation of alanine aminotransferase and vomiting during therapy were observed more frequently in the BAL + EDTA group compared with the DMSA + EDTA group. CONCLUSIONS: Treatment with DMSA or BAL combined with EDTA results in a comparable reduction in BPb.

Alanine Transaminase↗
PubMed1998

Soluble interleukin-2 receptor in children with reflux nephropathy.

PURPOSE: Serum soluble interleukin-2 receptor level is a sensitive and quantitative marker of lymphocyte activation. We determined levels of serum soluble interleukin-2 receptor in children with reflux nephropathy to evaluate its clinical significance in the prediction for the progression of renal injuries. MATERIALS AND METHODS: Serum soluble interleukin-2 receptor values were determined in 63 children with reflux nephropathy. The group consisted of 37 boys and 26 girls 10 to 18 years old. T cells (naive and memory), B cells and macrophages were evaluated immunohistochemically in the scarred kidneys of 4 other patients (3 boys and 1 girl 5 to 16 years old) who underwent nephrectomy due to severe reflux nephropathy with little function seen on (99m)technetium-dimercapto-succinic acid (DMSA) renal scan. Levels of serum soluble interleukin-2 receptor were measured by an enzyme-linked immunosorbent assay. We simultaneously determined serum levels of creatinine and beta2-microglobulin, and urinary levels of alpha1-microglobulin and microalbumin. Individual functions of the right and left kidneys were estimated by renal dimercaptosuccinic acid uptake. RESULTS: Levels of serum soluble interleukin-2 receptor in the patients who had low total uptake of DMSA (right uptake plus left uptake) were significantly higher than those from patients with normal total uptake. Levels of serum soluble interleukin-2 receptor correlated significantly with levels of creatinine (r=0.616, p <0.0001) and beta2-microglobulin (r=0.803, p <0.0001), and levels of urinary alpha1-microglobulin (r=0.753, p <0.0001) and microalbumin (r=0.673, p <0.0001). A significant negative correlation was observed between levels of serum soluble interleukin-2 receptor and total DMSA uptake values (right uptake plus left uptake r=-0.678, p <0.0001). In the scarred kidneys leukocyte infiltrates were markedly increased in fibrosed spaces. The predominant cell type in these lesions was memory T cells. CONCLUSIONS: These results suggest that elevated levels of serum soluble interleukin-2 receptor are likely to reflect activated T cells in the kidneys of patients with reflux nephropathy and may be a useful predictor of progression of renal injury in these children.

Adolescent↗