Application of Path Analysis to Urinary Findings of Cadmium-Induced Renal Dysfunction

Abe, Toshiyuki; Kobayashi, Etsuko; Okubo, Yasushi; Suwazono, Yasushi; Kido, Teruhiko; Shaikh, Zahir A.; Nogawa, Kôji

doi:10.1081/ese-100000473

Cited by 10 publications

(8 citation statements)

References 9 publications

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“…As a result of the widespread use of Cd in industry and its extensive dissemination in the environment, much attention has been focused on the identification of urinary biomarkers of the early stages of Cd-nephrotoxicity (Abe et al, 2001; Bernard, 2004; Mueller et al, 1998; Nakajima et al, 2005; Roels et al, 1999; Shaikh and Smith, 1986). Some of the urinary biomarkers that have been used for this purpose include the Cd-binding protein metallothionein (Shaikh et al, 1990), low molecular weight proteins such as β-2 microglobulin (Lauwerys et al, 1984) and Clara cell protein-16 (CC-16) (Bernard et al, 1994), and even Cd itself (Bernard, 2004; Mueller et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of novel urinary biomarkers of cadmium nephrotoxicity

Prozialeck

Edwards

Vaidya

et al. 2009

Toxicology and Applied Pharmacology

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As a result of the widespread use of Cd in industry and its extensive dissemination in the environment, there has been considerable interest in the identification of early biomarkers of Cd-induced kidney injury. Kim-1 is a transmembrane glycoprotein that is not detectable in normal kidney, but is upregulated and shed into the urine following ischemic or nephrotoxic injury. Recent studies utilizing a sub-chronic model of Cd exposure in the rat have shown that Kim-1 is an early urinary marker of Cd-induced kidney injury. Kim-1 was detected in the urine 4-5 weeks before the onset of proteinuria and 1-3 weeks before the appearance of urinary metallothionein and Clara cell protein 16, which are standard markers of Cd nephrotoxicity. In the present study, we have compared the time course for the appearance of Kim-1 in the urine with the time course for the appearance of alpha glutathione-S-transferase (α-GST), N-acetyl-β-D-glucoseamidase (NAG) and Cd, each of which have been used or proposed as urinary markers of Cd nephrotoxicity. Adult male Sprague-Dawley rats were given daily subcutaneous injections of 0.6 mg (5.36 μmoles)/kg Cd, 5 days per week for up to 12 weeks. One day each week, 24 hour urine samples were collected and analyzed for protein, creatinine and the various markers. The results showed that significant levels of Kim-1 appeared in the urine as early as 6 weeks into the treatment protocol and then continued to rise for the remainder of the 12 week treatment period. By contrast, significant levels of α-GST and NAG did not appear in the urine until 8 and 12 weeks, respectively, while proteinuria was not evident until 10 weeks. The urinary excretion of Cd was below the level of detection until week 4 and then showed a slow, linear increase over the next 6 weeks before increasing markedly between weeks 10 and 12. These results provide additional evidence that Kim-1 is a sensitive biomarker of the early stages of Cd-induced proximal tubule injury.

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Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of novel urinary biomarkers of cadmium nephrotoxicity

Prozialeck

Edwards

Vaidya

et al. 2009

Toxicology and Applied Pharmacology

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“…For example, the urinary excretion of metallothionein is a marker of Cd exposure as well as proximal tubular injury, but identifying the critical level of urinary metallothionein to indicate the onset of tubular injury has been problematic. 16,19,21,22,28,35,36 Moreover, it is not totally clear if increases in the urinary excretion of b 2 -microglobulin and CC-16 are solely markers of tubular dysfunction, or are a reflection of the blood levels of the proteins, which can be influenced by actions of toxicants on organs other than the kidney. 21 Kidney injury molecule-1 (Kim-1), which is also known as hepatitis A virus cellular receptor 1 (Havcr1), 37 is a type I transmembrane protein that is not detectable in normal kidney tissue, but is expressed at high levels in dedifferentiated proximal tubule epithelial cells after ischemic or toxic injury.…”

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confidence: 97%

“…10,16,23,31 b 2 -Microglobulin has been widely utilized in monitoring human populations for early signs of Cd-induced renal dysfunction. 16,19,32,33 Although CC-16 has not been widely used as a marker of Cd toxicity in humans, it has been used for this purpose in experimental studies in rats, where it has been shown to be comparable to b 2 -microglobulin as a marker of Cd nephrotoxicity. 34 While these markers have been used to monitor Cd toxicity in humans and experimental animals, several problems remain.…”

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confidence: 99%

“…21 Kidney injury molecule-1 (Kim-1), which is also known as hepatitis A virus cellular receptor 1 (Havcr1), 37 is a type I transmembrane protein that is not detectable in normal kidney tissue, but is expressed at high levels in dedifferentiated proximal tubule epithelial cells after ischemic or toxic injury. 16,38,39 It has been proposed that Kim-1 functions as a regulator of cell-cell adhesion at a time when the dedifferentiated regenerating cells of the injured proximal tubule relocate to denuded patches of the basement membrane and reform a continuous epithelial layer. 40 This process is associated with the proteolytic cleavage of the ectodomain of Kim-1 into the urine.…”

mentioning

confidence: 99%

“…[12][13][14][15] As a result of its ability to accumulate Cd and its sensitivity to injury, the kidney is, in effect, a sentinel of Cd exposure, and much attention has been focused on the identification of urinary biomarkers of the early stages of Cd nephrotoxicity. [16][17][18][19][20][21] Some of the biomarkers that have been used for this purpose include metallothionein, 22 b 2 -microglobulin, 10 and CC-16. 23 Metallothionein is a specific metal binding protein that plays a role in delivering Cd to the epithelial cells of the proximal tubule.…”

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Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity

Prozialeck

Vaidya

Liu

et al. 2007

Kidney International

195

149

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Cadmium (Cd) exposure results in injury to the proximal tubule characterized by polyuria and proteinuria. Kidney injury molecule-1 (Kim-1) is a transmembrane glycoprotein not normally detected in the mature kidney, but is upregulated and shed into the urine following nephrotoxic injury. In this study, we determine if Kim-1 might be a useful early biomarker of Cd nephrotoxicity. Male Sprague-Dawley rats were given daily injections of Cd for up to 12 weeks. Weekly urine samples were analyzed for Kim-1, protein, creatinine, metallothionein, and Clara cell protein CC-16. Significant levels of Kim-1 were detected in the urine by 6 weeks and continued to increase throughout the treatment period. This appearance of Kim-1 occurred 4-5 weeks before the onset of proteinuria, and 1-3 weeks before the appearance of metallothionein and CC-16. Higher doses of Cd gave rise to higher Kim-1 excretion. Reverse transcriptase-polymerase chain reaction (RT-PCR) expression analysis showed that Kim-1 transcript levels were increased after 6 weeks at the low dose of Cd. Immunohistochemical analysis showed that Kim-1 was present in proximal tubule cells of the Cd-treated rats. Our results suggest that Kim-1 may be a useful biomarker of early stages of Cd-induced proximal tubule injury.

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Evaluation of factors associated with cadmium exposure and kidney function in the general population

Huang

Choi

Kim

et al. 2011

Environmental Toxicology

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Cadmium (Cd) is a nonessential toxic metal which is widely distributed in the environment. The general population is exposed to low levels of Cd and the kidney is the organ most sensitive to Cd toxicity. This study was performed to simultaneously evaluate Cd exposure, kidney function, and oxidative stress biomarkers in the general population. A total of 643 adults were interviewed to document demographic characteristics, lifestyles, past-medical history, and diet during the last 24 h. We estimated daily Cd intake based on the diet of study subjects who had not been exposed to Cd occupationally. Whole blood and urine samples were collected and analyzed to determine Cd concentrations and kidney function indices (β₂ -microglobulin [β₂-MG], N-acetyl-β-D-glucosaminidase [NAG], metallothionein [MT]). The oxidative stress index (malondialdehyde [MDA]) was determined from the urine. The daily Cd intake from diet was established as 7.07 μg/day. The mean concentration of Cd measured in the blood was 1.22 μg/L and urine was 0.95 μg/g creatinine. The concentrations of Cd in blood and urine were higher in females than in males. The blood levels of Cd were affected by sex, age, and smoking, and urine Cd was influenced by sex, age, and blood Cd. The urine Cd was positively correlated with MT, NAG activity, and MDA in females, but with NAG only in males. The blood Cd was associated with MT in males. Increased NAG activity was observed when Cd in urine reached 1.0 μg Cd/g creatinine and was also affected by age, hypertension, and diabetes mellitus. Urinary MT only responded to Cd in urine or blood. In summary, exposure to Cd in the general population was influenced by various factors including sex, age, and smoking habits. Such exposure might eventually cause tubular damage in the kidneys through the oxidative stress mechanism, and females might be more susceptible than males to Cd exposure under the environment.

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Application of Path Analysis to Urinary Findings of Cadmium-Induced Renal Dysfunction

Cited by 10 publications

References 9 publications

Preclinical evaluation of novel urinary biomarkers of cadmium nephrotoxicity

Preclinical evaluation of novel urinary biomarkers of cadmium nephrotoxicity

Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity

Evaluation of factors associated with cadmium exposure and kidney function in the general population

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