Cd nephrotoxicity

Liu J, Liu Y, Klaassen CD. Nephrotoxicity of CdCI2 and Cd-metallothionein in cultured rat kidney proximal tubules and LLC-PK1 cells. Toxicol AppI Pharmacol 1994 128 264-270. 

Chronic intoxication by Cd was first described by Friberg in Sweden, and was subsequently confirmed by a number of workers in other countries (see the reviews by Friberg et al., 1986 Bernard and Lauwerys, 1986 IPCS, 1992 Bernard et al., 1992). The studies confirmed that the earliest manifestation of Cd nephrotoxicity is renal dysfunction, leading to increased proteinuria. Cd nephropathy is irreversible and may accelerate the age-related decline of renal function. Depending on the indicator of renal dysfunction used, critical concentrations of Cd in urine vary between 5 and 10 pg g creatinine, and the corresponding concentrations in the renal cortex range from 140 to 180 mg kg (Bernard et al., 1992). 

Functionally, urinary markers of Cd nephrotoxicity can be classified into 3 groups (1) Cd and Cd-binding proteins such as MT, (2) low-molecular-weight proteins, and (3) proteins and enzymes derived from the brush border, intraceUular organelles or the cytosol of proximal tubule epithelial cells. 

In mammals, cadmium inhibits copper absorption across the intestinal mucosa (Aaseth and Norseth 1986). Intercorrelations of copper with cadmium and zinc in livers of polar bears (Ursus maritimus) are probably mediated by metallothioneins, which may contain all three metals (Braune etal. 1991). In rats, copper protects against nephrotoxicity induced by cadmium, provided that copper is administered 24 h prior to cadmium insult. Specifically, rats given 12.5 mg Cu/kg BW by way of subcutaneous injection 24 h before receiving 0.4 mg Cd/kg BW — when compared to a group receiving Cd alone — did not have excessive calcium in urine and renal cortex or excessive protein in urine. Thus, 2.8 mg Cu/kg BW protects against 0.25 mg Cd/kg BW (Liu et al. 1992). 

S. G. E. Hart, W. P. Beierschmitt, J. B. Bartolone, D. S. Wyand, E. A. Kharrallah, S. D. Cohen, Evidence Against Deacetylation and for Cytochrome P450-Mediated Activation in Acetaminophen-Induced Nephrotoxicity in the CD-I Mouse , Toxicol. Appl. Pharmacol. 1991, 107, 1-15. 

Jaffe DR, Hassall CD, Brendel K. 1983. In wVoand in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene. J Toxicol Environ Health 11 857-867. 

Two of the natural CDs are known to be parenterally unsafe due to nephrotoxic effects [9], The etiology of the nephrotoxicity of a- and P-CD is unknown but is believed to be related to either CD uptake by kidney tubule cells resulting in disruption of intracellular function or the extraction of lipid membrane components by the CDs. The latter is suggested to be of validity since there seems to be a linear correlation between the ability of some CDs to disrupt cellular membranes and kidney nephrotoxicity [2, 6], The ability of CDs to cause red blood cell hemolysis and membrane irritation seems also to correlate with their ability to extract lipid membrane components cholesterol and phospholipids [10,11],... 

Renal Issues. The parent CDs can all show a toxic effect on the kidney when given parenterally. The nephrotoxicity of a- and p-CD manifests itself as a series of alterations in the organelles of the proximal tubule cells. ° The toxicity is initially expressed as an increase in apical vacuoles, which is typical of an adaptive response tothe excretion of osmotic agents at extremely high concentrations. This effect reverses upon discontinuation of CD administration. However, there are also other cellular changes not typical of... 

Kureishi A, Jewesson PJ, Rubinger M, Cole CD, Reece DE, Phillips GL, Smith JA, Chow AW. Double-blind comparison of teicoplanin versus vancomycin in febrile neutropenic patients receiving concomitant tobramycin and piperacillin effect on cyclosporin A-associated nephrotoxicity. Antimicrob Agents Chemother 1991 35(ll) 2246-52. 

Katholi RE, Taylor GJ, McCann WP, Woods WT, Jr., Womack KA, McCoy CD, Katholi CR, Moses HW, Mishkel GJ, Lucore CL, et al. Nephrotoxicity from contrast media attenuation with theophylline. Radiology 195 17-22,1995... 

Levine BS, Henry MC, Port CD, Richter WR, UrbanekMA. Nephrotoxic potential ofcis-diamminedichloroplatinum and four analogs in male Fischer 344 rats. J Natl Cancer Inst. 1981 Jul 67[1] 201-6... 

Flombaum CD. Gemcitabine Nephrotoxicity and the Hemolytic Uremic Syndrome (HUS) Report of 29 Cases from a Single Institution. J Am Soc Nephrol, 2005, 777°. Poster SA-PO1008. 

Kim CD, Cho YJ, ParkSFI, Fla SW, Lee EG, Kim YJ, KwonTFI, Kim IS, Kim YL. Urinary transforming growth factor-beta-induced gene-h3 (betaig-h3) as a sensitive predictor in chronic cyclosporine nephrotoxicity.Transplant Proc 2006 38 1314-1319. 

It has long been recognized that Cd exposure either after inhalation or ingestion, can give rise to nephrotoxicity in humans and that this effect is usually considered to be the earhest and most important health effect [32]. 

Liu J, liu Y, Habeebu SM, Waalkes MP, Klaassen CD. Chronic combined exposure to cadmium and arsenic exacerbates nephrotoxicity, particularly in metallothionein-l/ll null mice. Toxicology 2000,147 157-166. 

The mechanism of acute acetaminophen nephrotoxicity is related to the bioactivation of acetaminophen and/or its metabolites to highly reactive species which are capable of arylating renal macromolecules or generating reactive oxygen species. Acetaminophen hepatotoxicity is the result of conversion of acetaminophen to the reactive intermediate N-acetyl-p-benzoquinoneimine (NAPQI), which can covalently bind to hepatic macromolecules. It is less clear what role formation of NAPQI in the kidney plays in acetaminophen nephrotoxicity. In some species (e.g., the Fischer 344 rat) deacetylation appears to be an important biotransformation step in acetaminophen nephrotoxicity, while in other species (e.g., the CD-I mouse), bioactivation does not appear to require deacetylation of acetaminophen before the ultimate nephrotoxicant species is produced. Therefore, the role of NAPQI in acute acetaminophen nephrotoxicity might be species dependent. 

Parker RA, Bennett WM. Porter GA. Animal models in the study of aminoglycoside nephrotoxicity. In The aminoglycosides microbiology, clinical use and toxicology. Whelton A, Neu HC (editors). Marcel Dekker Inc, New York, Basel, 1982 235-268. Nicolau DP, Freeman CD, Belliveau PR Experience with once-daily aminoglycoside program administrated to 2184 adult patients. Antimicrob. Agent Chemother 1995 39 650-655. 

Lord G, Tagore R, Cook T, Gower P, Pusey CD. Nephropathy caused by Chinese herbs in the UK. Lancet 1999 354 481-482. Moore RD, Smith CR, Lipsky JJ, Mellitus ED, Lietman PS. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984 100 352-373. 

The future holds great promise for unraveling nephrotoxic mechanisms and understanding various aspects of clinical management. To enhance informa hon transfer we decided to pubhsh a CD as a companion to this book. Further into the futiue we plan to develop annual updates to supplement the text information and insure the reader is current in this rapidly evolving field. 

The natural cyclodextrins, a-, P and y-CD, have been chemically modified either to effect stronger complexation or to improve their safety. a-CD and P-CD cannot be used parenterally because of their nephrotoxicity. Recently, a number of modified cyclodextrins, including 2-hydroxypropyl-p-cyclodextrin (HP-P-CD) and sulfobutylether P-cyclodexhins [mainly (SBEVP-CD, CaptisoP], have been tested. They show better safety profiles than does P-CD. 

Because of its nephrotoxicity causing the Itai-Itai disease in humans, its teratogenic effects, its interactions with iron, copper and zinc, and its potentially existing can-cerogenic effects, cadmium (Cd) belongs to... 

Goyee RA, Weinbeeg CD, Victeey WM and Millee CR (1989) Lead-induced nephrotoxicity calcium as an indicator of tubular injury In Bach PH and Lock EA, eds. Nephrotoxicity extrapolation from in vitro to in vivo and from animals to man, pp. 11-20. Plenum Press, London. 

None of the mentioned renal effect parameters are specific for Cd. Other nephrotoxic agents such as mercury, chromium, lead, organic solvents and pesticides may also induce changes into these parameters (Herber et al., 1988). Table 1 gives an overview of the most common tubular and glomerular proteins, and tubular enzymes connected with Cd. 

Stern ST, Bruno MK, Hennig GE, Horton RA, Roberts JC, Cohen SD. Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-I mice I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine. Toxicol Appl Pharmacol 152005 202(2) 151-159. 

---