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Early biomarkers of cadmium exposure and nephrotoxicity

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Abstract

As the risks of cadmium (Cd)-induced kidney disease have become increasingly apparent, much attention has been focused on the development and use of sensitive biomarkers of Cd nephrotoxicity. The purpose of this review is to briefly summarize the current state of Cd biomarker research. The review includes overviews of the toxicokinetics of Cd, the mechanisms of Cd-induced proximal tubule injury, and mechanistic summaries of some of the biomarkers (N-acetyl-β-d-glucosamidase; β2-microglubulin, metallothionein, etc.) that have been most widely used in monitoring of human populations for Cd exposure and nephrotoxicity. In addition, several novel biomarkers (kidney injury molecule-1, α-glutathione-S-transferase and insulin) that offer the potential for improved biomonitoring of Cd-exposed populations are discussed.

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References

  • Afridi HI, Kazi TG, Kazi N, Jamali MK, Arain MB, Jalbani N, Baig JA, Sarfraz RA (2008) Evaluation of status of toxic metals in biological samples of diabetes mellitus patients. Diabetes Res Clin Pract 80:280–288

    Article  PubMed  CAS  Google Scholar 

  • Akesson A, Lundh T, Vahter M, Bjellerup P, Lidfeldt J, Nerbrand C, Samsioe G, Stromberg U, Skerfving S (2005) Tubular and glomerular kidney effects in Swedish women with low environmental cadmium exposure. Environ Health Perspect 113:1627–1631

    Article  PubMed  Google Scholar 

  • Alfven T, Jarup L, Elinder CG (2002) Cadmium and lead in blood in relation to low bone mineral density and tubular proteinuria. Environ Health Perspect 110:699–702

    Article  PubMed  CAS  Google Scholar 

  • ATSDR (2008a) Case Studies in Environmental Medicine (CSEM) Cadmium Toxicity. http://www.atsdr.cdcgov/csem/cadmium/cdlaboratory_evaluation.html

  • ATSDR (2008b) Toxicological Profile for Cadmium. http://www.atsdr.cdc.gov/cercla/toxprofiles/tp5.html

  • Bailly V, Zhang Z, Meier W, Cate R, Sanicola M, Bonventre JV (2002) Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J Biol Chem 277:39739–39748

    Article  PubMed  CAS  Google Scholar 

  • Bandara JM, Senevirathna DM, Dasanayake DM, Herath V, Bandara JM, Abeysekara T, Rajapaksha KH (2008) Chronic renal failure among farm families in cascade irrigation systems in Sri Lanka associated with elevated dietary cadmium levels in rice and freshwater fish (Tilapia). Environ Geochem Health 30:465–478

    Article  PubMed  CAS  Google Scholar 

  • Barbier O, Jacquillet G, Tauc M, Cougnon M, Poujeol P (2005) Effect of heavy metals on, and handling by, the kidney. Nephron Physiol 99:105–110

    Article  CAS  Google Scholar 

  • Barr DB, Wilder LC, Caudill SP, Gonzalez AJ, Needham LL, Pirkle JL (2005) Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements. Environ Health Perspect 113:192–200

    Article  PubMed  CAS  Google Scholar 

  • Bell RR, Early JL, Nonavinakere VK, Mallory Z (1990) Effect of cadmium on blood glucose level in the rat. Toxicol Lett 54:199–205

    Article  PubMed  CAS  Google Scholar 

  • Bernard A (2004) Renal dysfunction induced by cadmium: biomarkers of critical effects. Biometals 17:519–523

    Article  PubMed  CAS  Google Scholar 

  • Bernard A (2008) Cadmium & its adverse effects on human health. Indian J Med Res 128:557–564

    PubMed  CAS  Google Scholar 

  • Bernard A, Hermans C (1997) Biomonitoring of early effects on the kidney or the lung. Sci Total Environ 199:205–211

    Article  PubMed  CAS  Google Scholar 

  • Bernard A, Lauwerys R (1995) Low-molecular-weight proteins as markers of organ toxicity with special reference to Clara cell protein. Toxicol Lett 77:145–151

    Article  PubMed  CAS  Google Scholar 

  • Bernard A, Viau C, Lauwerys R (1983) Renal handling of human beta 2-microglobulin in normal and cadmium-poisoned rats. Arch Toxicol 53:49–57

    Article  PubMed  CAS  Google Scholar 

  • Bernard AM, Vyskocil AA, Mahieu P, Lauwerys RR (1987) Assessment of urinary retinol-binding protein as an index of proximal tubular injury. Clin Chem 33:775–779

    PubMed  CAS  Google Scholar 

  • Bernard AM, Thielemans NO, Lauwerys RR (1994) Urinary protein 1 or Clara cell protein: a new sensitive marker of proximal tubular dysfunction. Kidney Int Suppl 47:S34–S37

    PubMed  CAS  Google Scholar 

  • Biomarkers Definition Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95

    Article  Google Scholar 

  • Bonventre JV (2003) Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J Am Soc Nephrol 14(Suppl 1): S55–S61

    Google Scholar 

  • Bridges CC, Zalups RK (2005) Molecular and ionic mimicry and the transport of toxic metals. Toxicol Appl Pharmacol 204:274–308

    Article  PubMed  CAS  Google Scholar 

  • Broeckaert F, Clippe A, Knoops B, Hermans C, Bernard A (2000) Clara cell secretory protein (CC16): features as a peripheral lung biomarker. Ann N Y Acad Sci 923:68–77

    Article  PubMed  CAS  Google Scholar 

  • Buchet JP, Heilier JF, Bernard A, Lison D, Jin T, Wu X, Kong Q, Nordberg G (2003) Urinary protein excretion in humans exposed to arsenic and cadmium. Int Arch Occup Environ Health 76:111–120

    PubMed  CAS  Google Scholar 

  • Byrne C, Divekar SD, Storchan GB, Parodi DA, Martin MB (2009) Cadmium–a metallohormone? Toxicol Appl Pharmacol 238:266–271

    Article  PubMed  CAS  Google Scholar 

  • Casalino E, Sblano C, Calzaretti G, Landriscina C (2006) Acute cadmium intoxication induces alpha-class glutathione S-transferase protein synthesis and enzyme activity in rat liver. Toxicology 217:240–245

    Article  PubMed  CAS  Google Scholar 

  • Chang X, Jin T, Chen L, Nordberg M, Lei L (2009) Metallothionein I isoform mRNA expression in peripheral lymphocytes as a biomarker for occupational cadmium exposure. Exp Biol Med (Maywood) 234:666–672

    Article  CAS  Google Scholar 

  • Chen L, Jin T, Huang B, Chang X, Lei L, Nordberg GF, Nordberg M (2006a) Plasma metallothionein antibody and cadmium-induced renal dysfunction in an occupational population in China. Toxicol Sci 91:104–112

    Article  PubMed  CAS  Google Scholar 

  • Chen L, Jin T, Huang B, Nordberg G, Nordberg M (2006b) Critical exposure level of cadmium for elevated urinary metallothionein–an occupational population study in China. Toxicol Appl Pharmacol 215:93–99

    Article  PubMed  CAS  Google Scholar 

  • Chen L, Lei L, Jin T, Nordberg M, Nordberg GF (2006c) Plasma metallothionein antibody, urinary cadmium, and renal dysfunction in a Chinese type 2 diabetic population. Diabetes Care 29:2682–2687

    Article  PubMed  CAS  Google Scholar 

  • Choudhury H, Mudipalli A (2008) Potential considerations & concerns in the risk characterization for the interaction profiles of metals. Indian J Med Res 128:462–483

    PubMed  CAS  Google Scholar 

  • Crinnion WJ (2009a) The benefit of pre- and post-challenge urine heavy metal testing: part 2. Altern Med Rev 14:103–108

    PubMed  Google Scholar 

  • Crinnion WJ (2009b) The benefits of pre- and post-challenge urine heavy metal testing: Part 1. Altern Med Rev 14:3–8

    PubMed  Google Scholar 

  • de Burbure C, Buchet JP, Leroyer A, Nisse C, Haguenoer JM, Mutti A, Smerhovsky Z, Cikrt M, Trzcinka-Ochocka M, Razniewska G, Jakubowski M, Bernard A (2006) Renal and neurologic effects of cadmium, lead, mercury, and arsenic in children: evidence of early effects and multiple interactions at environmental exposure levels. Environ Health Perspect 114:584–590

    Article  PubMed  CAS  Google Scholar 

  • Edwards JR, Prozialeck WC (2009) Cadmium, diabetes and chronic kidney disease. Toxicol Appl Pharmacol 238:289–293

    Article  PubMed  CAS  Google Scholar 

  • Edwards JR, Lamar PC, Prozialeck WC (2008) Upregulation of glyceraldehyde 3 phosphate dehydrogenase (GAPDH) and glucose 6 phosphate dehydrogenase (G6PDH) during the early stages of cadmium induced renal injury. The Toxicologist CD—An official Journal of the Society of Toxicology 102:Abstract #458

  • FDA (2008) European Medicines Agency to Consider Additional Test Results when Assessing New Drug Safety. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01850.html

  • Fels LM (1999) Risk assessment of nephrotoxicity of cadmium. Ren Fail 21:275–281

    Article  PubMed  CAS  Google Scholar 

  • Ferguson MA, Vaidya VS, Bonventre JV (2008) Biomarkers of nephrotoxic acute kidney injury. Toxicology 245:182–193

    Article  PubMed  CAS  Google Scholar 

  • Fowler BA (2009) Monitoring of human populations for early markers of cadmium toxicity: a review. Toxicol Appl Pharmacol 238:294–300

    Article  PubMed  CAS  Google Scholar 

  • Friedman LS, Lukyanova EM, Kundiev YI, Shkiryak-Nizhnyk ZA, Chislovska NV, Mucha A, Zvinchuk AV, Oliynyk I, Hryhorczuk D (2006) Anthropometric, environmental, and dietary predictors of elevated blood cadmium levels in Ukrainian children: Ukraine ELSPAC group. Environ Res 102:83–89

    Article  PubMed  CAS  Google Scholar 

  • Fuhr BJ, Rabenstein DL (1973) Nuclear magnetic resonance studies of the solution chemistry of metal complexes. IX. The binding of cadmium, zinc, lead, and mercury by glutathione. J Am Chem Soc 95:6944–6950

    Article  PubMed  CAS  Google Scholar 

  • Garcon G, Leleu B, Zerimech F, Marez T, Haguenoer JM, Furon D, Shirali P (2004) Biologic markers of oxidative stress and nephrotoxicity as studied in biomonitoring of adverse effects of occupational exposure to lead and cadmium. J Occup Environ Med 46:1180–1186

    Article  PubMed  CAS  Google Scholar 

  • Garcon G, Leleu B, Marez T, Zerimech F, Haguenoer JM, Furon D, Shirali P (2007) Biomonitoring of the adverse effects induced by the chronic exposure to lead and cadmium on kidney function: usefulness of alpha-glutathione S-transferase. Sci Total Environ 377:165–172

    Article  PubMed  CAS  Google Scholar 

  • Gobe GC, Endre ZH (2003) Cell death in toxic nephropathies. Semin Nephrol 23:416–424

    Article  PubMed  CAS  Google Scholar 

  • Gonick HC (2008) Nephrotoxicity of cadmium & lead. Indian J Med Res 128:335–352

    PubMed  CAS  Google Scholar 

  • Goyer RA, Miller CR, Zhu SY, Victery W (1989) Non-metallothionein-bound cadmium in the pathogenesis of cadmium nephrotoxicity in the rat. Toxicol Appl Pharmacol 101:232–244

    Article  PubMed  CAS  Google Scholar 

  • Halatek T, Gromadzinska J, Wasowicz W, Rydzynski K (2005) Serum clara-cell protein and beta2-microglobulin as early markers of occupational exposure to nitric oxides. Inhal Toxicol 17:87–97

    Article  PubMed  CAS  Google Scholar 

  • Han JC, Park SY, Hah BG, Choi GH, Kim YK, Kwon TH, Kim EK, Lachaal M, Jung CY, Lee W (2003) Cadmium induces impaired glucose tolerance in rat by down-regulating GLUT4 expression in adipocytes. Arch Biochem Biophys 413:213–220

    Article  PubMed  CAS  Google Scholar 

  • Hantson P, Bernard A, Hermans C (2008) Kinetics and determinants of the changes of CC16, a lung secretory protein in a rat model of toxic lung injury. Clin Toxicol (Phila) 46:230–238

    CAS  Google Scholar 

  • Haswell-Elkins M, Satarug S, O’Rourke P, Moore M, Ng J, McGrath V, Walmby M (2008) Striking association between urinary cadmium level and albuminuria among Torres Strait Islander people with diabetes. Environ Res 106:379–383

    Article  PubMed  CAS  Google Scholar 

  • He L, Wang B, Hay EB, Nebert DW (2009) Discovery of ZIP transporters that participate in cadmium damage to testis and kidney. Toxicol Appl Pharmacol 238:250–257

    Article  PubMed  CAS  Google Scholar 

  • Hellstrom L, Elinder CG, Dahlberg B, Lundberg M, Jarup L, Persson B, Axelson O (2001) Cadmium exposure and end-stage renal disease. Am J Kidney Dis 38:1001–1008

    Article  PubMed  CAS  Google Scholar 

  • Hotz P, Buchet JP, Bernard A, Lison D, Lauwerys R (1999) Renal effects of low-level environmental cadmium exposure: 5-year follow-up of a subcohort from the Cadmibel study. Lancet 354:1508–1513

    Article  PubMed  CAS  Google Scholar 

  • Huang J (2004) Chinese National health standards for occupational exposure to cadmium and diagnostic criteria of occupational chronic cadmium poisoning. Biometals 17:511

    Article  CAS  Google Scholar 

  • IARC (1993) Cadmium and cadmium compounds. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. IARC Monogr Eval Carcinog Risks Hum 58:119–237

    Google Scholar 

  • Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Duffield JS, Bonventre JV (2008) Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest 118:1657–1668

    Article  PubMed  CAS  Google Scholar 

  • Ikeda M, Ezaki T, Tsukahara T, Moriguchi J, Furuki K, Fukui Y, Okamoto S, Ukai H, Sakurai H (2003) Bias induced by the use of creatinine-corrected values in evaluation of beta2-microgloblin levels. Toxicol Lett 145:197–207

    Article  PubMed  CAS  Google Scholar 

  • Jarup L (2002) Cadmium overload and toxicity. Nephrol Dial Transplant 17(Suppl 2): 35–39

    Google Scholar 

  • Jarup L, Akesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238:201–208

    Article  PubMed  CAS  Google Scholar 

  • Jarup L, Alfven T (2004) Low level cadmium exposure, renal and bone effects–the OSCAR study. Biometals 17:505–509

    Article  PubMed  Google Scholar 

  • Jarup L, Berglund M, Elinder CG, Nordberg G, Vahter M (1998) Health effects of cadmium exposure—a review of the literature and a risk estimate. Scand J Work Environ Health 24(Suppl 1): 1–51

    Google Scholar 

  • Jarup L, Hellstrom L, Alfven T, Carlsson MD, Grubb A, Persson B, Pettersson C, Spang G, Schutz A, Elinder CG (2000) Low level exposure to cadmium and early kidney damage: the OSCAR study. Occup Environ Med 57:668–672

    Article  PubMed  CAS  Google Scholar 

  • Jin T, Lu J, Nordberg M (1998) Toxicokinetics and biochemistry of cadmium with special emphasis on the role of metallothionein. Neurotoxicology 19:529–535

    PubMed  CAS  Google Scholar 

  • Jin T, Nordberg G, Wu X, Ye T, Kong Q, Wang Z, Zhuang F, Cai S (1999) Urinary N-acetyl-beta-D-glucosaminidase isoenzymes as biomarker of renal dysfunction caused by cadmium in a general population. Environ Res 81:167–173

    Article  PubMed  CAS  Google Scholar 

  • Joseph P (2009) Mechanisms of cadmium carcinogenesis. Toxicol Appl Pharmacol 238:272–279

    Article  PubMed  CAS  Google Scholar 

  • Kawada T (1995) Indicators of renal effects of exposure to cadmium: N-acetyl-beta-D-glucosaminidase and others. Sangyo Eiseigaku Zasshi 37:69–73

    PubMed  CAS  Google Scholar 

  • Kita K, Miura N, Yoshida M, Yamazaki K, Ohkubo T, Imai Y, Naganuma A (2006) Potential effect on cellular response to cadmium of a single-nucleotide A–> G polymorphism in the promoter of the human gene for metallothionein IIA. Hum Genet 120:553–560

    Article  PubMed  CAS  Google Scholar 

  • Kjellstrom T (1986) Renal effects. In: Friberg L, Elinder C-G, Kjellstrom T, Nordberg GF (eds) Cadmium and health: a toxicological and epidemiological appraisal. CRC Press, Boca Raton, pp 21–109

    Google Scholar 

  • Klaassen CD, Liu J (1997) Role of metallothionein in cadmium-induced hepatotoxicity and nephrotoxicity. Drug Metab Rev 29:79–102

    Article  PubMed  CAS  Google Scholar 

  • Klaassen CD, Liu J, Choudhuri S (1999) Metallothionein: an intracellular protein to protect against cadmium toxicity. Annu Rev Pharmacol Toxicol 39:267–294

    Article  PubMed  CAS  Google Scholar 

  • Klaassen CD, Liu J, Diwan BA (2009) Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol 238:215–220

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi E, Suwazono Y, Uetani M, Inaba T, Oishi M, Kido T, Nishijo M, Nakagawa H, Nogawa K (2006) Estimation of benchmark dose as the threshold levels of urinary cadmium, based on excretion of total protein, beta2-microglobulin, and N-acetyl-beta-D-glucosaminidase in cadmium nonpolluted regions in Japan. Environ Res 101:401–406

    Article  PubMed  CAS  Google Scholar 

  • Kobryn A, Pacsa A, White AG, Kumar MS, Abouna GM (1989) Are peripheral blood lymphocytes the source of elevated B-2-microglobulin in renal transplant recipients? Transplant Proc 21:302–303

    PubMed  CAS  Google Scholar 

  • Koyama H, Satoh H, Suzuki S, Tohyama C (1992) Increased urinary cadmium excretion and its relationship to urinary N-acetyl-beta-D-glucosaminidase activity in smokers. Arch Toxicol 66:598–601

    Article  PubMed  CAS  Google Scholar 

  • Lash LH, Zalups RK (1992) Mercuric chloride-induced cytotoxicity and compensatory hypertrophy in rat kidney proximal tubular cells. J Pharmacol Exp Ther 261:819–829

    PubMed  CAS  Google Scholar 

  • Lauwerys RR, Bernard AM, Roels HA, Buchet JP (1994) Cadmium: exposure markers as predictors of nephrotoxic effects. Clin Chem 40:1391–1394

    PubMed  CAS  Google Scholar 

  • Lei LJ, Jin TY, Zhou YF (2007) Insulin expression in rats exposed to cadmium. Biomed Environ Sci 20:295–301

    PubMed  CAS  Google Scholar 

  • Lieberthal W, Koh JS, Levine JS (1998) Necrosis and apoptosis in acute renal failure. Semin Nephrol 18:505–518

    PubMed  CAS  Google Scholar 

  • Liu Y, Liu J, Habeebu SM, Waalkes MP, Klaassen CD (2000) Metallothionein-I/II null mice are sensitive to chronic oral cadmium-induced nephrotoxicity. Toxicol Sci 57:167–176

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Qu W, Kadiiska MB (2009) Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicol Appl Pharmacol 238:209–214

    Article  PubMed  CAS  Google Scholar 

  • Mannino DM, Holguin F, Greves HM, Savage-Brown A, Stock AL, Jones RL (2004) Urinary cadmium levels predict lower lung function in current and former smokers: data from the Third National Health and Nutrition Examination Survey. Thorax 59:194–198

    Article  PubMed  CAS  Google Scholar 

  • Martelli A, Rousselet E, Dycke C, Bouron A, Moulis JM (2006) Cadmium toxicity in animal cells by interference with essential metals. Biochimie 88:1807–1814

    Article  PubMed  CAS  Google Scholar 

  • Menke A, Muntner P, Silbergeld EK, Platz EA, Guallar E (2009) Cadmium levels in urine and mortality among US adults. Environ Health Perspect 117:190–196

    PubMed  CAS  Google Scholar 

  • Merali Z, Singhal RL (1975) Protective effect of selenium on certain hepatotoxic and pancreotoxic manifestations of subacute cadmium administration. J Pharmacol Exp Ther 195:58–66

    PubMed  CAS  Google Scholar 

  • Merali Z, Singhal RL (1980) Diabetogenic effects of chronic oral cadmium administration to neonatal rats. Br J Pharmacol 69:151–157

    PubMed  CAS  Google Scholar 

  • Miura N (2009) Individual susceptibility to cadmium toxicity and metallothionein gene polymorphisms: with references to current status of occupational cadmium exposure. Ind Health 47:487–494

    Article  PubMed  CAS  Google Scholar 

  • Moriguchi J, Ezaki T, Tsukahara T, Furuki K, Fukui Y, Okamoto S, Ukai H, Sakurai H, Shimbo S, Ikeda M (2003) Comparative evaluation of four urinary tubular dysfunction markers, with special references to the effects of aging and correction for creatinine concentration. Toxicol Lett 143:279–290

    Article  PubMed  CAS  Google Scholar 

  • Moriguchi J, Inoue Y, Kamiyama S, Horiguchi M, Murata K, Sakuragi S, Fukui Y, Ohashi F, Ikeda M (2009a) N-acetyl-beta-D-glucosaminidase (NAG) as the most sensitive marker of tubular dysfunction for monitoring residents in non-polluted areas. Toxicol Lett 190:1–8

    Article  PubMed  CAS  Google Scholar 

  • Moriguchi J, Inoue Y, Kamiyama S, Sakuragi S, Horiguchi M, Murata K, Fukui Y, Ohashi F, Ikeda M (2009b) Cadmium and tubular dysfunction marker levels in urine of residents in non-polluted areas with natural abundance of cadmium in Japan. Int Arch Occup Environ Health (Epub ahead of print)

  • Mueller PW (1993) Detecting the renal effects of cadmium toxicity. Clin Chem 39:743–745

    PubMed  CAS  Google Scholar 

  • Mueller PW, MacNeil ML, Steinberg KK (1989) N-acetyl-beta-D-glucosaminidase assay in urine: urea inhibition. J Anal Toxicol 13:188–190

    PubMed  CAS  Google Scholar 

  • Mueller PW, Price RG, Finn WF (1998) New approaches for detecting thresholds of human nephrotoxicity using cadmium as an example. Environ Health Perspect 106:227–230

    Article  PubMed  CAS  Google Scholar 

  • Nakajima M, Kobayashi E, Suwazono Y, Uetani M, Oishi M, Inaba T, Kido T, Shaikh ZA, Nogawa K (2005) Excretion of urinary cadmium, copper, and zinc in cadmium-exposed and nonexposed subjects, with special reference to urinary excretion of beta2-microglobulin and metallothionein. Biol Trace Elem Res 108:17–31

    Article  PubMed  CAS  Google Scholar 

  • Navas-Acien A, Tellez-Plaza M, Guallar E, Muntner P, Silbergeld E, Jaar B, Weaver V (2009) Blood cadmium and lead and chronic kidney disease in US adults: a joint analysis. Am J Epidemiol 170:1156–1164

    Article  PubMed  Google Scholar 

  • Nawrot TS, Van HE, Thijs L, Richart T, Kuznetsova T, Jin Y, Vangronsveld J, Roels HA, Staessen JA (2008) Cadmium-related mortality and long-term secular trends in the cadmium body burden of an environmentally exposed population. Environ Health Perspect 116:1620–1628

    Article  PubMed  CAS  Google Scholar 

  • Noonan CW, Sarasua SM, Campagna D, Kathman SJ, Lybarger JA, Mueller PW (2002) Effects of exposure to low levels of environmental cadmium on renal biomarkers. Environ Health Perspect 110:151–155

    Article  PubMed  CAS  Google Scholar 

  • Nordberg M (1984) General aspects of cadmium: transport, uptake and metabolism by the kidney. Environ Health Perspect 54:13–20

    Article  PubMed  CAS  Google Scholar 

  • Nordberg GF (2004) Cadmium and health in the 21st century–historical remarks and trends for the future. Biometals 17:485–489

    Article  PubMed  CAS  Google Scholar 

  • Nordberg GF (2009) Historical perspectives on cadmium toxicology. Toxicol Appl Pharmacol 238:192–200

    Article  PubMed  CAS  Google Scholar 

  • Nordberg GF, Kjellstrom T, Nordberg G (1986) Kinetics and metabolism. In: Friberg L, Elinder CG, Kjellstrom T, Nordberg GF (eds) Cadmium and health: a toxicological and epidemiological appraisal. CRC Press, Boca Raton, pp 103–178

    Google Scholar 

  • Nordberg GF, Jin T, Hong F, Zhang A, Buchet JP, Bernard A (2005) Biomarkers of cadmium and arsenic interactions. Toxicol Appl Pharmacol 206:191–197

    Article  PubMed  CAS  Google Scholar 

  • OSHA (1999) Substance Safety Data Sheet- Cadmium—1910.1027 App. http://www.oshagov/pls/oshaweb/owadispshow_document?p_table=standar

  • Pinot F, Kreps SE, Bachelet M, Hainaut P, Bakonyi M, Polla BS (2000) Cadmium in the environment: sources, mechanisms of biotoxicity, and biomarkers. Rev Environ Health 15:299–323

    PubMed  CAS  Google Scholar 

  • Poulik MD, Gold P, Shuster J (1979) beta 2-Microglobulin: methods and clinical applications. CRC Crit Rev Clin Lab Sci 10:225–245

    Article  PubMed  CAS  Google Scholar 

  • Prozialeck WC, Edwards JR (2007) Cell adhesion molecules in chemically-induced renal injury. Pharmacol Ther 114:74–93

    Article  PubMed  CAS  Google Scholar 

  • Prozialeck WC, Lamar PC, Lynch SM (2003) Cadmium alters the localization of N-cadherin, E-cadherin, and beta-catenin in the proximal tubule epithelium. Toxicol Appl Pharmacol 189:180–195

    Article  PubMed  CAS  Google Scholar 

  • Prozialeck WC, Vaidya VS, Liu J, Waalkes MP, Edwards JR, Lamar PC, Bernard AM, Dumont X, Bonventre JV (2007) Kidney injury molecule-1 is an early biomarker of cadmium nephrotoxicity. Kidney Int 72:985–993

    Article  PubMed  CAS  Google Scholar 

  • Prozialeck WC, Edwards JR, Lamar PC, Liu J, Vaidya VS, Bonventre JV (2009a) Expression of kidney injury molecule-1 (Kim-1) in relation to necrosis and apoptosis during the early stages of Cd-induced proximal tubule injury. Toxicol Appl Pharmacol 238:306–314

    Article  PubMed  CAS  Google Scholar 

  • Prozialeck WC, Edwards JR, Vaidya VS, Bonventre JV (2009b) Preclinical evaluation of novel urinary biomarkers of cadmium nephrotoxicity. Toxicol Appl Pharmacol 238:301–305

    Article  PubMed  CAS  Google Scholar 

  • Rabenstein DL (1989) Metal complexes of glutathione and their biological significance. In: Dolphin D, Auromovie O, Poulson R (eds) Glutathione: chemical, biochemical and medical aspects. Wiley, New York, pp 147–186

    Google Scholar 

  • Racusen LC (1993) Tubular injury in human kidneys: pathologic findings and pathogenic mechanisms. Clin Investig 71:858–860

    Article  PubMed  CAS  Google Scholar 

  • Roels H, Bernard A, Buchet JP, Goret A, Lauwerys R, Chettle DR, Harvey TC, Haddad IA (1979) Critical concentration of cadmium in renal cortex and urine. Lancet 1:221

    Article  PubMed  CAS  Google Scholar 

  • Roels HA, Hoet P, Lison D (1999) Usefulness of biomarkers of exposure to inorganic mercury, lead, or cadmium in controlling occupational and environmental risks of nephrotoxicity. Ren Fail 21:251–262

    Article  PubMed  CAS  Google Scholar 

  • Satarug S, Moore MR (2004) Adverse health effects of chronic exposure to low-level cadmium in foodstuffs and cigarette smoke. Environ Health Perspect 112:1099–1103

    Article  PubMed  CAS  Google Scholar 

  • Satarug S, Baker JR, Urbenjapol S, Haswell-Elkins M, Reilly PE, Williams DJ, Moore MR (2003) A global perspective on cadmium pollution and toxicity in non-occupationally exposed population. Toxicol Lett 137:65–83

    Article  PubMed  CAS  Google Scholar 

  • Satoh M, Koyama H, Kaji T, Kito H, Tohyama C (2002) Perspectives on cadmium toxicity research. Tohoku J Exp Med 196:23–32

    Article  PubMed  CAS  Google Scholar 

  • Scherer G, Barkemeyer H (1983) Cadmium concentrations in tobacco and tobacco smoke. Ecotoxicol Environ Saf 7:71–78

    Article  PubMed  CAS  Google Scholar 

  • Schulz C, Angerer J, Ewers U, Heudorf U, Wilhelm M (2009) Revised and new reference values for environmental pollutants in urine or blood of children in Germany derived from the German environmental survey on children 2003–2006 (GerES IV). Int J Hyg Environ Health 212:637–647

    Article  PubMed  CAS  Google Scholar 

  • Schwartz GG, Il’yasova D, Ivanova A (2003) Urinary cadmium, impaired fasting glucose, and diabetes in the NHANES III. Diabetes Care 26:468–470

    Article  PubMed  CAS  Google Scholar 

  • Shaikh ZA, Smith LM (1986) Biological indicators of cadmium exposure and toxicity. Exp Suppl 50:124–130

    CAS  Google Scholar 

  • Shaikh ZA, Tohyama C (1984) Urinary metallothionein as an indicator of cadmium body burden and of cadmium-induced nephrotoxicity. Environ Health Perspect 54:171–174

    Article  PubMed  CAS  Google Scholar 

  • Shaikh ZA, Tohyama C, Nolan CV (1987) Occupational exposure to cadmium: effect on metallothionein and other biological indices of exposure and renal function. Arch Toxicol 59:360–364

    Article  PubMed  CAS  Google Scholar 

  • Shaikh ZA, Ellis KJ, Subramanian KS, Greenberg A (1990) Biological monitoring for occupational cadmium exposure: the urinary metallothionein. Toxicology 63:53–62

    Article  PubMed  CAS  Google Scholar 

  • Shaikh ZA, Vu TT, Zaman K (1999) Oxidative stress as a mechanism of chronic cadmium-induced hepatotoxicity and renal toxicity and protection by antioxidants. Toxicol Appl Pharmacol 154:256–263

    Article  PubMed  CAS  Google Scholar 

  • Soden SE, Lowry JA, Garrison CB, Wasserman GS (2007) 24-hour provoked urine excretion test for heavy metals in children with autism and typically developing controls, a pilot study. Clin Toxicol (Phila) 45:476–481

    CAS  Google Scholar 

  • Squibb KS, Fowler BA (1984) Intracellular metabolism and effects of circulating cadmium-metallothionein in the kidney. Environ Health Perspect 54:31–35

    Article  PubMed  CAS  Google Scholar 

  • Staessen JA, Buchet JP, Ginucchio G, Lauwerys RR, Lijnen P, Roels H, Fagard R (1996) Public health implications of environmental exposure to cadmium and lead: an overview of epidemiological studies in Belgium. Working Groups. J Cardiovasc Risk 3:26–41

    Article  PubMed  CAS  Google Scholar 

  • Sundberg A, Appelkvist EL, Dallner G, Nilsson R (1994) Glutathione transferases in the urine: sensitive methods for detection of kidney damage induced by nephrotoxic agents in humans. Environ Health Perspect 102(Suppl 3): 293–296

    Google Scholar 

  • Suwazono Y, Akesson A, Alfven T, Jarup L, Vahter M (2005) Creatinine versus specific gravity-adjusted urinary cadmium concentrations. Biomarkers 10:117–126

    Article  PubMed  CAS  Google Scholar 

  • Suwazono Y, Sand S, Vahter M, Filipsson AF, Skerfving S, Lidfeldt J, Akesson A (2006) Benchmark dose for cadmium-induced renal effects in humans. Environ Health Perspect 114:1072–1076

    Article  PubMed  CAS  Google Scholar 

  • Suzuki Y (1980) Cadmium metabolism and toxicity in rats after long-term subcutaneous administration. J Toxicol Environ Health 6:469–482

    Article  PubMed  CAS  Google Scholar 

  • Tang J, Xiao T, Wang S, Lei J, Zhang M, Gong Y, Li H, Ning Z, He L (2009) High cadmium concentrations in areas with endemic fluorosis: a serious hidden toxin? Chemosphere 76:300–305

    Article  PubMed  CAS  Google Scholar 

  • Tanimoto A, Hamada T, Koide O (1993) Cell death and regeneration of renal proximal tubular cells in rats with subchronic cadmium intoxication. Toxicol Pathol 21:341–352

    Article  PubMed  CAS  Google Scholar 

  • Teeyakasem W, Nishijo M, Honda R, Satarug S, Swaddiwudhipong W, Ruangyuttikarn W (2007) Monitoring of cadmium toxicity in a Thai population with high-level environmental exposure. Toxicol Lett 169:185–195

    Article  PubMed  CAS  Google Scholar 

  • Thevenod F (2003) Nephrotoxicity and the proximal tubule. Insights from cadmium. Nephron Physiol 93:87–93

    Article  CAS  Google Scholar 

  • Thevenod F (2009) Cadmium and cellular signaling cascades: to be or not to be? Toxicol Appl Pharmacol 238:221–239

    Article  PubMed  CAS  Google Scholar 

  • Thomas LD, Hodgson S, Nieuwenhuijsen M, Jarup L (2009) Early kidney damage in a population exposed to cadmium and other heavy metals. Environ Health Perspect 117:181–184

    PubMed  CAS  Google Scholar 

  • Trisak ST, Doumgdee P, Rode BM (1990) Binding of zinc and cadmium to human serum albumin. Int J Biochem 22:977–981

    Article  PubMed  CAS  Google Scholar 

  • Trzcinka-Ochocka M, Jakubowski M, Razniewska G, Halatek T, Gazewski A (2004) The effects of environmental cadmium exposure on kidney function: the possible influence of age. Environ Res 95:143–150

    Article  PubMed  CAS  Google Scholar 

  • Uno T, Kobayashi E, Suwazono Y, Okubo Y, Miura K, Sakata K, Okayama A, Ueshima H, Nakagawa H, Nogawa K (2005) Health effects of cadmium exposure in the general environment in Japan with special reference to the lower limit of the benchmark dose as the threshold level of urinary cadmium. Scand J Work Environ Health 31:307–315

    PubMed  CAS  Google Scholar 

  • Vaidya VS, Ferguson MA, Bonventre JV (2008) Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol 48:463–493

    Article  PubMed  CAS  Google Scholar 

  • Vaidya VS, Ford GM, Waikar SS, Wang Y, Clement MB, Ramirez V, Glaab WE, Troth SP, Sistare FD, Prozialeck WC, Edwards JR, Bobadilla NA, Mefferd SC, Bonventre JV (2009) A rapid urine test for early detection of kidney injury. Kidney Int 76:108–114

    Article  PubMed  CAS  Google Scholar 

  • Waalkes MP (2003) Cadmium carcinogenesis. Mutat Res 533:107–120

    PubMed  CAS  Google Scholar 

  • Waisberg M, Joseph P, Hale B, Beyersmann D (2003) Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology 192:95–117

    Article  PubMed  CAS  Google Scholar 

  • Wang G, Fowler BA (2008) Roles of biomarkers in evaluating interactions among mixtures of lead, cadmium and arsenic. Toxicol Appl Pharmacol 233:92–99

    Article  PubMed  CAS  Google Scholar 

  • Webb M (1979) Functions of hepatic and renal metallothioneins in the control of the metabolism of cadmium and certain other bivalent cations. Exp Suppl 34:313–320

    CAS  Google Scholar 

  • Webb M (1986) Role of metallothionein in cadmium metabolism. In: Foulkes EC (ed) Cadmium, hanbook of experimental pharmcology. Springer-Verlag, New York, pp 281–337

    Google Scholar 

  • World Health Organization (WHO) (2000) Cadmium. http://www.euro.who.int/document/aiq/6_3cadmium.pdf

  • Wu X, Jin T, Wang Z, Ye T, Kong Q, Nordberg G (2001) Urinary calcium as a biomarker of renal dysfunction in a general population exposed to cadmium. J Occup Environ Med 43:898–904

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Su S, Zhai R, Chen K, Jin T, Huang B, Zhou Y, Ge X, Wei G, Liao R (2004) Lack of reversal effect of EDTA treatment on cadmium induced renal dysfunction: a fourteen-year follow-up. Biometals 17:435–441

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Liang Y, Jin T, Ye T, Kong Q, Wang Z, Lei L, Bergdahl IA, Nordberg GF (2008) Renal effects evolution in a Chinese population after reduction of cadmium exposure in rice. Environ Res 108:233–238

    Article  PubMed  CAS  Google Scholar 

  • Xiao W, Liu Y, Templeton DM (2009) Pleiotropic effects of cadmium in mesangial cells. Toxicol Appl Pharmacol 238:315–326

    Article  PubMed  CAS  Google Scholar 

  • Yoshida M, Ohta H, Yamauchi Y, Seki Y, Sagi M, Yamazaki K, Sumi Y (1998) Age-dependent changes in metallothionein levels in liver and kidney of the Japanese. Biol Trace Elem Res 63:167–175

    Article  PubMed  CAS  Google Scholar 

  • Zalups RK, Ahmad S (2003) Molecular handling of cadmium in transporting epithelia. Toxicol Appl Pharmacol 186:163–188

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Portions of the work described in this review were supported by Grant R01-ES006478 from the National Institute of Environmental Health Sciences. The authors sincerely thank Victoria Sears and Laura Phelps for their assistance in preparing the manuscript.

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  1. Department of Pharmacology, Midwestern University, 555 31st Street, Downers Grove, IL, 60515, USA

    Walter C. Prozialeck & Joshua R. Edwards

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  1. Walter C. Prozialeck
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  2. Joshua R. Edwards
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Correspondence to Walter C. Prozialeck.

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Prozialeck, W.C., Edwards, J.R. Early biomarkers of cadmium exposure and nephrotoxicity. Biometals 23, 793–809 (2010). https://doi.org/10.1007/s10534-010-9288-2

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