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PubMed2003

Resistive index in febrile urinary tract infections: predictive value of renal outcome.

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 intrarenal resistive index (RI). We evaluated its ability to predict renal involvement as assessed by dimercaptosuccinic acid (DMSA) scintigraphy. In total 157 patients admitted to the pediatric department of the Sişli Etfal Hospital with clinical signs of febrile UTI were included in the study. The children were divided into groups according to their age at the time of ultrasonography (US). RI was measured from the renal arteries with Doppler US in the first 72 h in all 157 children. Renal involvement was assessed by (99m)Tc-DMSA scintigraphy in the first 7 days after admission. The examination was repeated at least 6 months later if the first result was abnormal. All available patients with an abnormal scintigraphy underwent voiding cystourethrography 4-6 weeks after the acute infection. All patients with vesicoureteral reflux and scarred kidneys were excluded from the study. DMSA scintigraphy demonstrated abnormal changes in 114 of 157 children and was normal in the remaining 43 children. Of these 114 children, 104 underwent repeat scintigraphy, of whom 77 showed partially or totally reversible lesion(s). Of these 77 children, 17 children (22%) with vesicoureteral reflux were excluded. Thus, we compared the 43 children with lower UTI with the 60 children with definite acute pyelonephritis at admission. Kidneys with changes of acute pyelonephritis had a mean RI of 0.744+/-0.06 in infants, 0.745+/-0.03 in preschool children, and 0.733+/-0.09 in patients of school age with upper UTI. However, the mean RI was 0.703+/-0.06 in infants, 0.696+/-0.1 in preschool children, and 0.671+/-0.09 in school-aged patients with lower UTI. The mean RI values were significantly higher in patients with upper UTI ( P<0.001). There was a highly significant correlation between RI values and the severity of the renal lesion as ranked by DMSA scintigraphy ( P<0.001). When the cut-off RI value was 0.715, there was an 80% sensitivity and a 89% specificity for diagnosing upper UTI. Refluxing kidneys and scarred kidneys also had higher RI values. In conclusion, RI values were increased significantly in children with febrile UTI when renal parenchymal involvement (assessed by DMSA scintigraphy) was present. Our results also support the view that the children with high RI values are at a high risk of reflux, scarring, or both, which was frequently observed in febrile UTI. This might allow identification of patients at risk for severe renal lesions that require more aggressive therapy, investigation, and follow-up than those with lower UTI.

Child↗
PubMed2003

Ultrasonography in the evaluation of renal scarring using DMSA scan as the gold standard.

Dimercaptosuccinic acid (DMSA) renal scan is presently the technique of choice for assessing renal scars. Recent advances suggest that ultrasonography could replace DMSA scan for this purpose. This paper describes the experience of a tertiary pediatric referral hospital performing ultrasonography and DMSA scans in the assessment of renal scarring. Investigations were conducted 3-6 months after patients presented with urinary tract infection (UTI). Results were extracted from the radiology information system and recorded for analysis. All children with a UTI who had undergone DMSA and ultrasound examination on the same day between January 1995 and December 1999 were included; 930 kidneys were compared. DMSA scan was utilized as the reference method. When used to detect focal renal scarring, ultrasonography had a sensitivity of 5.2%, specificity of 98.3%, a positive predictive value (PPV) of 50% and a negative predictive value (NPV) of 75.8%. When used to detect diffuse renal scarring, ultrasonography had a sensitivity of 47.2%, specificity of 91.8%, PPV of 60.8% and NPV of 86.6%. Our results demonstrate that although ultrasonography has a good specificity for the detection of renal scarring compared with DMSA, it has low sensitivity, PPV and NPV. Ultrasonography cannot be substituted for DMSA scan in the evaluation of focal renal scarring.

Child↗
PubMed1996

Poor renal uptake of 99mtechnetium-dimercaptosuccinic acid and near-normal 99mtechnetium-mercaptoacetyltriglycine renogram in nephronophthisis.

Four patients with the clinical diagnosis of nephronophthisis are presented, all having a very poor renal uptake of 99mtechnetium-dimercaptosuccinic acid (99mTc-DMSA) but clearly visualized kidneys on early images with 99mtechnetium-mercaptoacetyltriglycine and a normal or almost normal renogram. There was no difference between a young patient in an early stage of the disease and the other three patients with more advanced renal disease. In contrast, a patient with tubulointerstitial nephritis with uveitis had considerably better renal uptake of 99mTc-DMSA despite impaired renal function. We suggest that the specific tubular function defect in nephronophthisis might be the cause of the poor uptake of 99mTc-DMSA. We also recommend the method to support the clinical suspicion of nephronophthisis, even in the early stages of the disease.

Adolescent↗
PubMed1997

The evaluation of acute pyelonephritis and renal scarring with technetium 99m-dimercaptosuccinic acid renal scintigraphy: evolving concepts and future directions.

Technetium 99m-dimercaptosuccinic acid (DMSA) scintigraphy has emerged as the imaging agent of choice for the detection and evaluation of acute pyelonephritis and renal cortical scarring in children. Consequently, DMSA scintigraphy provides a unique opportunity to study the progression of renal damage and functional loss from the initial insult of acute pyelonephritis to the subsequent development of irreversible renal scarring. Over the last few years, clinical and experimental investigations using DMSA renal scintigraphy have provided new insights into the etiology, pathophysiology, and clinical outcome of acute pyelonephritis in children. These studies have confirmed the primary role of the acute inflammatory response, associated with both reflux and nonreflux pyelonephritis, in the etiology of irreversible renal scarring. Furthermore, several studies have shown that renal scarring can be prevented or diminished by the early diagnosis and treatment of pyelonephritis. This review highlights these recent observations and makes recommendations regarding current clinical and future research applications.

Humans↗
PubMed2000

The etiology of renal scars in infants with pyelonephritis and vesicoureteral reflux.

We aimed to investigate, by means of dimercaptosuccinic acid (DMSA) scan, the relations between vesicoureteral reflux (VUR) and its degree, pyelonephritis during infancy, and renal parenchymal findings. Seventy-four infants with pyelonephritis, 44 girls and 30 boys (mean age at their first pyelonephritic episode 4.12 months, median 3 months), were enrolled in the study. Voiding cystourethrography (VCU) and ultrasonography (US) were performed within 6 weeks following the infection. DMSA was performed at least 4 months after the urinary tract infection (UTI). The renal parenchymal pathology was defined as focal or multifocal defects or as a split renal uptake of less than 45%. DMSA scintigraphy revealed that 19% (14/74) of the children had renal damage. Renal parenchymal findings were observed only when VUR was present, and its grade was above 3/5. No abnormality was found in 51 renal units without reflux, 9 with VUR grade 1/5, and 54 with grade 2/5. Renal pathology was observed in 9/24 renal units with VUR grade 3, 3/8 with grade 4, and 2/2 with grade 5. No correlation was found between renal parenchymal defects and clinical presentation of the pyelonephritis, type of the microorganism, presence of bacteremia, or the number of recurrent infections. In adequately treated infants, renal damage is probably due to a reflux-associated, preexisting, congenital renal parenchymal pathology and not to the inflammatory process. We suggest that DMSA scintigraphy should not be performed routinely in every infant with UTI and should be reserved primarily for children with VUR grade 3 and above.

Cicatrix↗
PubMed2001

Angiotensin converting enzyme gene polymorphism in primary vesicoureteral reflux.

We studied the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene in 78 patients with primary vesicoureteral reflux (VUR), and examined renal function by dimercaptosuccinate (DMSA) renoscintigraphy and diethylenetriamine-penta-acetic acid (DTPA) renogram in each genotype. Patients were classified into three genotypes according to the ACE gene I/D polymorphisms: 32 in II genotype, 36 in ID, and 10 in DD. The incidence of presumably congenital unilateral small kidneys was high in DD patients (70%). Glomerular filtration rate obtained from DTPA renogram was 120.7+/-35.7 ml/min (expressed as mean+/-SD) in II genotype, 111.7+/-33.3 in ID, and 88.0+/-18.0 in DD. The total quantitative DMSA tracer uptake of both kidneys was also low in patients with the D allele. This study shows that the D allele of ACE gene is closely related to small congenital kidneys with refluxing ureters in patients with primary VUR, and in accordance with previous reports, this allele is also related to the progression of reflux nephropathy.

Alleles↗
PubMed2001

Treatment of children with acute pyelonephritis: a prospective randomized study.

The aim of this study was to compare, in children with acute pyelonephritis, the efficacy of 7 days' (group A) and 3 days' (group B) intravenous antibiotics, both followed by an oral treatment. Children were randomized after 3 days of intravenous treatment. Technetium-99m dimercaptosuccinic acid (DMSA) scintigraphy was performed within the first days after admission and repeated 6 months later. Total or partial persistence of renal abnormalities on the 6-month DMSA scintigraphy was used as the endpoint of the study. Among the 92 children included in the study, 87 were followed for at least 6 months (43 in group A and 44 in group B) and were eligible for analysis. Late DMSA was abnormal in 9 kidneys of group A and 12 kidneys of group B, representing respectively 24% and 44% of kidneys with abnormalities on the initial DMSA (difference statistically not significant). When the patients were stratified according to the delay of treatment, the percentage of patients with sequelae in group A was comparable, whether the delay was less or more than 1 week. In group B, the percentage of patients with sequelae was significantly higher (P<0.01) when the delay was more than 1 week.

Acute Disease↗
PubMed2002

Age-related radiological imaging in children with acute pyelonephritis.

Accurate diagnosis of acute pyelonephritis (APN) using clinical and laboratory parameters is often difficult in children. The aims of this retrospective study were twofold. Firstly, to correlate the clinical and laboratory manifestations of APN with the results of the dimercaptosuccinic acid (DMSA) renal scan in different age groups. Secondly, to compare the DMSA renal scan, renal ultrasonography (RUS), and voiding cystourethrography (VCUG) in patients with clinical APN. The DMSA renal scan was utilized as the gold standard for renal involvement. We determined the sensitivity of these tests in febrile urinary tract infections (UTI) in three age groups: group I less than 2 years; group II 2-8 years; group III older than 8 years. During the period January 1992 through December 1998, 222 children presented with a febrile UTI. All patients had a DMSA renal scan, 208 had contrast VCUG, and 163 had RUS. The clinical and laboratory manifestation of pyelonephritis correlated better with a positive DMSA renal scan in the older children than in the younger children; 85% of the DMSA renal scans were positive in group III; 69% in group II; 48% in group I (P<0.001). Vesicoureteral reflux detected by contrast VCUG was more prevalent in the younger age groups. Although high grades of reflux (grade IV-V) correlated better with a positive DMSA renal scan, it did not reach a level of statistical significance (P>0.05). RUS did not correlate with a positive DMSA renal scan in any age group.

Acute Disease↗
PubMed2006

Response of arsenic-induced oxidative stress, DNA damage, and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats.

Arsenic and its compounds cause adverse health effects in humans. Current treatment employs administration of thiol chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), which facilitate its excretion from the body. However, these chelating agents are compromised by number of limitations due to their lipophobic nature, particularly in case of chronic poisoning. Combination therapy is a new approach to ensure enhanced removal of metal from the body, reduced doses of potentially toxic chelators, and no redistribution of metal from one organ to another, following chronic metal exposure. The present study attempts to investigate dose-related effects of two thiol chelators, DMSA and one of its new analogues, monoisoamyl dimercaptosuccinic acid (MiADMSA), when administered in combination with the aim of achieving normalization of altered biochemical parameters suggestive of oxidative stress and depletion of inorganic arsenic following chronic arsenic exposure. Twenty-five adult male Wistar rats were given 25 ppm arsenic for 10 weeks followed by chelation therapy with the above chelating agents at a dose of 0.3 mmol/kg (orally) when administered individually or 0.15 mmol/kg and 0.3 mmol/kg (once daily for 5 consecutive days), respectively, when administered in combination. Arsenic exposure led to the inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) activity and depletion of glutathione (GSH) level. These changes were accompanied by significant depletion of hemoglobin, RBC and Hct as well as blood superoxide dismutase (SOD) acitivity. There was an increase in hepatic and renal levels of thiobarbituric acid-reactive substances, while GSH:GSSG ratio decreased significantly, accompanied by a significant increase in metallothionein (MT) in hepatocytes. DNA damage based on denaturing polyacrylamide gel electrophoresis revealed significant loss in the integrity of DNA extracted from the liver of arsenic-exposed rats compared to that of normal animals. These changes were accompanied by a significant elevation in blood and soft-tissue arsenic concentration. Co-administration of DMSA and MiADMSA at lower dose (0.15 mmol/kg) was most effective not only in reducing arsenic-induced oxidative stress but also in depleting arsenic from blood and soft tissues compared to other treatments. This combination was also able to repair DNA damage caused following arsenic exposure. We thus recommend combined administration of DMSA and MiADMSA for achieving optimum effects of chelation therapy.

Animals↗
PubMed1987

Determination and metabolism of dithiol-chelating agents: electrolytic and chemical reduction of oxidized dithiols in urine.

The presence of oxidized species of the dithiol-chelating agents, meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS), in human urine was determined by chemical and electrolytic reduction methods. Urine from a human given either DMSA or DMPS was treated with electrolysis, dithiothreitol, or sodium tetrahydridoborate (NaBH4). The SH groups were derivatized with monobromobimane for the determination of unaltered dithiols. Total dithiol (unaltered and oxidized) was determined by reduction followed by derivatization with monobromobimane. The bimane derivatives were identified and quantified by HPLC and fluorescence. Although all three reduction methods gave similar results, electrolytic reduction of oxidized DMSA and chemical reduction with NaBH4 of oxidized DMPS are recommended based upon both day to day reproducibility and recovery of standards. After reduction a 4-fold increase in DMSA and a 20-fold increase in DMPS were found in urine by 12 h after an oral dose of DMSA or DMPS. These new methods for the determination of dithiols and their oxidized forms should lead to a better understanding of the metabolic properties of these increasingly important orally effective chelating agents.

Borohydrides↗
PubMed1989

Determination and metabolism of dithiol chelating agents. IV. Urinary excretion of meso-2,3-dimercaptosuccinic acid and mercaptosuccinic acid in rabbits given meso-2,3-dimercaptosuccinic acid.

The water-soluble dithiol chelating agents meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS) are becoming of increasing importance for the treatment of lead, arsenic and mercury poisoning. There is, however, a paucity of data about their metabolic transformation. Male rabbits were given DMSA (0.20 mmol/kg) i.m., and urine was collected over a 6-hr period. Monobromobimane derivatization, HPLC separation, and fluorescence detection, along with [U-14C]DMSA data, demonstrated that the total 14C found in the urine was distributed as 73% unaltered DMSA, 7% mercaptosuccinic acid and 6 and 14% of two unknowns. Electrolytic reductive treatment of the urine did not increase the urinary content of DMSA, indicating that oxidative biotransformation is not a major pathway for DMSA in the rabbit. This latter result is strikingly different from that for DMPS in rabbit.

Animals↗
PubMed1991

Methylene blue as an inhibitor of superoxide generation by xanthine oxidase. A potential new drug for the attenuation of ischemia/reperfusion injury.

Tissue oxidases, especially xanthine oxidase, have been proposed as primary sources of toxic oxygen radicals in many experimental models of disease states. Among these, ischemia-reperfusion injury may be of the greatest clinical interest. In this paper we propose the use of methylene blue as a means of suppressing the production of superoxide radicals O2- by acting as an alternative electron acceptor for xanthine oxidase. Previous work has indicated that methylene blue accepts electrons from xanthine oxidase at the iron-sulfur center. Initial experiments in our laboratory demonstrated that (1) pairs of electrons from each enzymatic oxidation are transferred to methylene blue, (2) the reduction of methylene blue can be achieved by model iron-sulfur centers, similar to the iron-sulfur center of xanthine oxidase, (3) reduced methylene blue auto-oxidizes to produce H2O2 directly, rather than O2-, and (4) methylene blue is effective at non-toxic levels (2-5 mg/kg) in preventing free radical damage to liver and kidney tissues in an in vitro model of ischemia and reoxygenation. Accordingly, we propose that methylene blue may represent a new class of antioxidant drugs that competitively inhibit reduction of molecular oxygen to superoxide by acting as alternative electron acceptors for tissue oxidases. We have termed these agents "parasitic" electron acceptors.

Animals↗
PubMed1995

In vitro inhibition of glutathione reductase by arsenotriglutathione.

Arsenotriglutathione, a product of the reaction of arsenate or arsenite with glutathione, is a mixed-type inhibitor (Ki = 0.34 mM) of the in vitro reduction of glutathione disulfide by purified yeast glutathione reductase. Notably, arsenotriglutathione was a 10-fold more potent inhibitor than either arsenite or glutathione. The inhibition of glutathione reductase by arsenotriglutathione was partly reversed by the addition of meso-2,3-dimercaptosuccinic acid (DMSA). However, high concentrations of DMSA also inhibited the reduction of glutathione disulfide by the yeast enzyme (IC50 of 7 mM with 0.1 mM glutathione disulfide). Ultrafiltration of the enzyme-arsenotriglutathione complex recovered about 74% of the original (non-inhibited) activity, suggesting that the inhibition of glutathione reductase by arsenotriglutathione had both reversible and irreversible components. The relatively high potency of arsenotriglutathione as an inhibitor of glutathione reductase may alter the reduction of glutathione disulfide and affect the availability of glutathione that is required for the reduction of arsenate to arsenite and for the formation of the arsenotriglutathione complex.

Animals↗