Early Markers of Nephrotoxicity: Detection of Children at Risk from Environmental Pollution

Price, Robert G.; Patel, Sharmila; Chivers, Ian; Milligan, Peter; Taylor, Sarah

doi:10.3109/08860229909085092

Cited by 11 publications

(5 citation statements)

References 6 publications

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“…NAG-B is an intralysosomal membrane-bound enzyme, which is released into urine when disruption of lysosomal membranes occurs. NAG-T and especially NAG-B were reported as highly sensitive indicators of Cd tubular toxicity, and thus they were recommended for the biological monitoring of exposure to this heavy metal (Bernard et al 1995;Mueller et al 1998;Jin et al 1999;Price et al 1999). The Cd-induced increase in NAG-T and NAG-B urinary activities considerably preceded the occurrence of changes in other biochemical markers of kidney status.…”

Section: Discussionmentioning

confidence: 95%

“…The nephrotoxicity of Cd has been extensively studied and widely reported in occupationally (Kahan et al 1992;Bernard et al 1995;Ja¨rup et al 2000) and environmentally (Jin et al 1999;Price et al 1999;Ja¨rup et al 2000) exposed human subjects, as well as in various experimental models (Aughey et al 1984;Nordberg et al 1994;Mitsumori et al 1998;Ohta et al 2000). However, reports concerning the simultaneous assessment of the structure and function of this organ and Cd accumulation are rare.…”

Section: Introductionmentioning

confidence: 97%

“…The level of Cd above which early effects occur is unknown. Thus, special attention has been paid to evaluation of safe levels of Cd exposure in humans, and to search for sensitive biomarkers allowing detection of early changes at the stage when they are still reversible (Mueller et al 1998;Jin et al 1999;Price at al. 1999;Roels et al 1999).…”

Section: Introductionmentioning

confidence: 99%

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Changes in the structure and function of the kidney of rats chronically exposed to cadmium. I. Biochemical and histopathological studies

et al. 2003

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The aim of this study was to assess the effects of chronic exposure to cadmium (Cd) on the structure and function of kidneys, as well as to establish the body burden of Cd at which the changes occur. For this purpose we have created an experimental model using rats intoxicated with Cd administered in drinking water at the concentration of 5 or 50 mg Cd/l for 6, 12 and 24 weeks. The degree of kidney damage was evaluated biochemically and histopathologically. Sensitive biomarkers of Cd-induced proximal tubular injury such as urinary total N-acetyl-beta- d-glucosaminidase (NAG-T) and its isoenzyme B (NAG-B), and alkaline phosphatase (ALP) were used. Cd content in the kidney increased with the level and duration of exposure leading to dose- and time-dependent structural and functional renal failure. In rats exposed to 5 mg Cd/l, first symptoms of injury of the main tubules of long and short nephrons (structural damage to epithelial cells, increased urinary activities of NAG-T and NAG-B) were noted after 12 weeks of the experiment. The damage occurred at a low kidney Cd concentration amounting to 4.08+/-0.33 micro g/g wet weight (mean +/-SE) and a urinary concentration of 4.31+/-0.28 micro g/g creatinine. On exposure to 50 mg Cd/l, damage to the main tubules (blurred structure of tubular epithelium, atrophy of brush border, partial fragmentation of cells with release of nuclei into tubular lumen as well as increased urinary activities of NAG-T, NAG-B and ALP) was already evident after 6 weeks with the kidney Cd concentration of 24.09+/-1.72 micro g/g wet weight. In rats exposed to 50 mg Cd/l, a lack of regular contour of glomeruli was noted after 12 weeks, whereas after 24 weeks thickening of capillary vessels and widening of filtering space were evident. After 24 weeks of exposure to Cd, increased urea concentration in the serum with simultaneous decrease in its level in the urine, indicating decreased clearance of urea, and increased excretion of total protein were observed, but endogenous creatinine clearance remained unaffected. At the lower exposure, symptoms of structural, but not functional, damage to the glomeruli were also evident after 24 weeks of the experiment. Our results provide evidence that chronic exposure to Cd dose-dependently damages (structurally and functionally) the whole kidney. The injury affects the main resorptive part (proximal convoluted tubules and straight tubules) and the filtering part (glomeruli) of the nephron. But the target site for Cd action is the main tubule. We hypothesize that the threshold for Cd effects on the kidney is less than 4.08+/-0.33 micro g/g wet kidney weight and greater than 2.40+/-0.15 micro g/g (at this Cd concentration no symptoms of kidney damage were noted), and it may be close to the latter value. A very important finding of this study is that Cd acts on the whole kidney, especially on the main tubules, even at relatively low accumulation in this organ. It confirms the hypothesis that humans environmentally exposed to Cd, especially smokers, are at risk of t...

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Changes in the structure and function of the kidney of rats chronically exposed to cadmium. I. Biochemical and histopathological studies

et al. 2003

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“…In addition to susceptibility due to genetic factors or the presence of disease, the sex and age of the individual should be considered. Children are particularly vulnerable to nephrotoxins and children living in areas of high industrial pollution exhibit clear signs of renal damage (Fels et al 1998;Price et al 1999a).…”

Section: Application Of Renal Biomarkersmentioning

confidence: 99%

Early Markers of Nephrotoxicity

Price

2002

Comp Clin Path

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The kidney is susceptible to a wide range of nephrotoxins which vary in their e¡ect from mild renal dysfunction to severe damage and end-stage renal failure. The identi¢cation of the presence of early renal damage, and also of individuals at risk of developing renal dysfunction, is important in order that corrective therapies can be applied at an early stage. However, glomerular ¢ltration rate (GFR) is unlikely to fall until 50% of nephrons have ceased to function. A major challenge is to provide measurements, both qualitative and quantitative, that give an early indication of the initial site of renal damage before gross deterioration in kidney function has occurred. Nephrotoxic exposure results in a cascade of events of gradually increasing severity. Initially, functional changes occur which, if exposure continues, then progress past a point of no return leading ultimately to renal failure. Most biomarkers measure the e¡ect of a toxin on the kidney, but some are insensitive, making it di⁄cult to measure accurately the extent to which the kidney has been exposed. Used selectively, biomarkers are able to give information on the stage and severity of the damage/disease process. To be useful, a biomarker should be easily measured by robust inexpensive procedures, which can be carried out on random or timed urine samples. The e¡ect of nephrotoxic agents is best assessed with a small battery of tests that can be followed by more specialized tests to con¢rm the severity and type of renal damage that has occurred.

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“…The interpretation of biomarkers in children and adolescents is different than that in adults. [42] Participants who were adolescents at baseline but 20 years of age or older at follow-up had almost no elevated biomarkers compared to the 40% found in the group <20 years of age at follow-up (the majority were still going through puberty). These findings agree with findings from other populations that found puberty-related biomarker changes.…”

Section: Discussionmentioning

confidence: 89%

Confirming the Utility of Four Kidney Biomarker Tests in a Longitudinal Follow-Up Study

Sarasua¹,

Mueller²,

Kathman³

et al. 2003

Renal Failure

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In this follow-up study, 526 persons were followed for almost 5 years to assess the reversibility and predictive value of four kidney biomarkers in a field epidemiology setting. This study examined (a) whether elevations in urinary albumin, N-acetyl-beta-D-glucosaminidase, retinol-binding protein, and alanine aminopeptidase remained elevated at follow-up and (b) whether these initial elevations were predictive of kidney disease (as measured by markers of kidney dysfunction: serum creatinine, serum cystatin C, creatinine clearance, and urine osmolality) at follow-up. Study participants were 8-76 years of age at baseline and were followed for an average of 4.5 years. Approximately 50% of adults who had an elevated biomarker did not have an elevation at followup. Youths with elevated biomarkers at baseline, but who completed adolescence by the time of the follow-up, no longer had any elevations in biomarkers at follow-up. Adult participants who had elevated biomarkers and selected health conditions at baseline (diabetes and, to a lesser extent, heart disease, hypertension, gout, and urinary tract disease) were more likely to show early indicators of kidney impairment at follow-up. Participants with these health conditions and normal kidney biomarker values at baseline had kidney test results at follow-up that were similar to results of study participants who did not have these health conditions at baseline. The presence or absence of elevated biomarkers at baseline among generally healthy participants was not associated with the development of early indicators of kidney impairment at follow-up. This longitudinal study confirmed the utility of these four kidney biomarker tests as markers of preclinical organ dysfunction among adults with certain preexisting medical conditions.

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Early Markers of Nephrotoxicity: Detection of Children at Risk from Environmental Pollution

Cited by 11 publications

References 6 publications

Changes in the structure and function of the kidney of rats chronically exposed to cadmium. I. Biochemical and histopathological studies

Changes in the structure and function of the kidney of rats chronically exposed to cadmium. I. Biochemical and histopathological studies

Early Markers of Nephrotoxicity

Confirming the Utility of Four Kidney Biomarker Tests in a Longitudinal Follow-Up Study

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