Nephrotoxicity histopathology

In male Fischer 344 rats treated intraperitoneally with 0, 10, 20, 40, 60 or 80 mg/kg bw acrylonitrile, significant increases in urinary volume and glucose were observed 24 h after treatment with 20 mg/kg bw (Rouisse et al., 1986). Increased levels of urinary N-acetyl-P-D-glucosaminidase were detected after treatment with 60 mg/kg bw acrylonitrile. Symptoms of nephrotoxicity were also observ ed after a 4-h exposure to 200 ppm [434 mg/m3] acrylonitrile. Histopathological examination revealed lesions in the proximal tubular region of the kidney. 

In animal studies of nephrotoxicity not only can histopathology be carried out but various biochemical parameters can be compared with those from untreated animals. They include lipid peroxidation and covalent binding to tissue macromolecules. 

Experimental exposiue of neomycin in calves has reported both nephrotoxicity and ototocity (demonstrated clinically). The clinical pathological observations included granular casts in urine, proteinuria and low specific gravity, azotemia, decreased creatinine clearance, polyuria, and polydipsia. The histopathological findings included renal tubular epithelial degeneration and necrosis (Crowell et al, 1981). 

Recently, a case of vulture mortality was reported from the Indian subcontinent related to NS AID toxicity. Diclofenac is a widely available veterinary NS AID in the Indian subcontinent, used in domestic livestock. Vultures were exposed to the drug when they consumed carcasses of cattle that were treated with diclofenac shortly before death. Experimental studies of this drug in vultures showed marked nephrotoxicity. The gross observations were primarily deposits of urate on the surface of internal organs related to renal failure. Histopathological findings were acute necrosis of the proximal renal tubular epithelium with minimal inflammatory response and deposits of urate crystals (Oaks et al, 2004 Meteyer et al, 2005). 

Citrinin is a benzopyran metabolite produced by the toxic strains of Pencillium ochraceus and Aspergillus verruco-sum. Some hepatotoxic effects have been reported for citrinin but the lethal effects are largely due to the nephrotoxicity. The specific mechanism of action in the kidneys is not known, but it leads to acute tubular necrosis. In pigs, rats, and rabbits, the proximal segments are affected. Histopathological findings in different species of animals... 

Other protease inhibitors have also been rarely associated with kidney injury. A single case of interstitial nephritis and reversible AKI in a patient treated with atazanavir has also been reported [153] Acute kidney injury attributed to ritonavir has been reported in several patients [154-157], the majority of whom were receiving concomitant nephrotoxic medications, while others had preexisting kidney disease or were volume depleted. In several patients, AKI recurred upon ritonavir rechallenge. Kidney biopsies were not performed, so histopathologic correlates and etiology of kidney injury were not precisely defined. 

Mihatsch MJ, Thiel G, Ryffel B. Histopathology of cyclosporine nephrotoxicity. Transplant Proc 1988 20 759-771. 

Davies DR, Bittmann I, Pardo J. Histopathology of calcineurin inhibitor-induced nephrotoxicity. Transplantation 2000 69 SSI 1-SS13. 

Potier M, Woif A, Cambar J. Comparative study of cyciosporin A, cyclosporin G, and the novel cyclosporin derivative IMM 125 in isoiated giomeruii and cuitured rat mesangiai ceiis a morphometric analysis. Nephrol Dial Transplant 1998 13 1406-1411. Mihatsch MJ, Thiel G, Ryffel B. Histopathology of cyclosporine nephrotoxicity. Transplant Proc 1988 20 759-771. 

Nephrotoxicity, manifested by glomerular and tubular histopathology, proteinuria, enzymuria, aminoaciduria, and increased renal metallothionein concentration, occurs in NiCl2-treated rats (Giditz et al. 1975, Kasprzak et al. 1986, Sunderman and Fraser 1983, Sunderman and Horak 1981). 

The second tier of tests is often implemented when there is suspicion or evidence of a nephrotoxic effect gained either from the initial urinalysis or histopathology. The focus is mainly on characterizing and identifying the affected regions of the using proteins, enzymes, electrolytes, or metabolites. A combination of protein, enzyme, and metabolite measurements can help to localize the site of renal injury. 

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