Toxicant-Induced Renal Injury

The species, dose and time needed to induce injury and the appropriate endpoints will vary with the toxicant selected. The following is an example of such a model Procedure  

Male Wistar rats with an initial weight of about 300 g receive a single intravenous dose of 2 mg/kg adriamycin. Twice a week during a 12-weeks period, the animals are weighed, 24-h urine is collected and blood pressure is measured by the tail-cuff method. 

During the first 5 weeks, all animals are kept on a low sodium diet with tap water ad libitum. After stabilization of proteinuria (5 weeks), animals are divided into two groups receiving either low sodium or normal sodium diet. After a week of stabilization on these diets, animals may be treated with test componds. 

The regimen is continued until the end of the study (week 12), at which time all animals are sacrificed and blood samples and kidney tissue are obtained. 

During each blood pressure measurement session, five measurements are recorded for each animal. The blood pressure is taken as the mean of the last 3 recordings. Urinary protein is determined by the Pyrogallol Red-molybdate method (RA-1000 Tech-nicon). Urinary sodium, creatinine and urea and serum electrolytes, creatinine, albumin, cholesterol and triacylglycerols are measured by a standard autoanalyser technique. Kidney samples are fixed in formalin and embedded in paraffin. Sections are stained with the periodic acid/Schiff technique. Focal glomerular sclerosis is scored semiquantitatively by light microscopy. 

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It should be noted that in the majority of the above mentioned studies, metal-induced renal injury was considered as if exposure occurred to only one metal at a time. In reality it is clear that environmental and occupational exposure may involve several metals at the same time and in varying concentrations [34]. It has been shown that with combined exposure various metals may interact with each other and that one metal may alter the potential toxicity of another in either a beneficial or deleterious way. As an example, whilst arsenic has been shown to worsen cadmium-induced nephrotoxicity, data from experimental studies have shown that selenium may protect against the renal effects induced by cadmium [52]. Other studies have shown that the iron status may alter the toxic effects of aluminium at the level of the bone and the parathyroid gland [53,54], whilst in a recent increased lead accumulation was associated with disturbances in the concentration of a number of essential trace elements [55]. 

A number of toxicants and drugs are known to induce renal injury resulting in acute renal failure, a prevalent clinical condition. These include... 

MODIFICATIONS OF THE METHOD Animal models with spontaneous disease exist and can be used in place of the toxicant-induced models. In addition, an investigator may take advantage of either genetically-modified animals or exploit strain differences in sensitivity to xenobiotics to examine mechanisms of renal injury. 

It is well known that a large number of chemical substances, including toxic metals and metalloids such as arsenic, cadmium, lead, and mercury, cause cell injury in the kidney. With metal-induced neurotoxicity, factors such as metal-binding proteins, inclusion bodies, and cell-specific receptor-like proteins seem to influence renal injury in animals and humans. It is of interest to note that certain renal cell populations become the targets for metal toxicity, while others do not. In fact, the target cell populations handle the organic and common inorganic nephrotoxicants differently. ... 

Sharing importance with individual susceptibihty is the previously mentioned concept of critical body burden of toxicant as a prerequisite for inducing renal cell injury. It is this concept of body burden that helps explain why the various clinical manifestations... 

Beta-lactam induced renal toxicity can results from their use in monotherapy or when used in combination with other nephrotoxic drugs such as aminoglycosides, amphotericin B, cisplatin, cyclosporine, furosemide, ifosfamide, vancomycin and nephrotoxic p-lactams. While the risk of nephrotoxic injury from monotherapy with p-lactams is relatively low, this risk is substantially increased when multiple drug combinations are required. 

The mechanisms responsible for the contractile responses to AmB have not been identified. Theoretically, the drug can act either directly on the vascular smooth muscle or through release of secondary mediators. A large number of studies have examined putative indirect mechanisms of action. Those studies have revealed that neither renal denervation nor angiotensin II receptor blockade prevent the renal vasoconstriction or the reduction in GFR [87, 88]. Although Cutaia et al [89] demonstrated a toxic effect of AmB on endothelial cells, endothelin does not appear to be involved in the acute responses to AmB [88, 90] and reduced nitric oxide synthesis, consequent to endothelial injury is not involved in modulation of AmB-induced renal vasoconstriction [88]. 

Cell death induced by AmB in the medullary thick ascending limb is prevented by ouabain [108]. A reasonable explanation for this observation is that ouabain, by inhibiting transport, decreases the oxygen demand of an area of the nephron that already has a hmited oxygen supply. This is consistent with the observation that AmB exhibits preferential damage to the medullary ray, an area that is vulnerable to hypoxic injury [48]. It is also conceivable that AmB-induced renal vasoconstriction and ischemia to this section of the nephron enhances cell death produced by a direct toxic action. Thus, any maneuver that improves renal perfusion, or decreases oxygen demand, would be expected to be protective. This may explain the salutary effect of salt loading, theophylline, calcium channel... 

Gordon JA, Gattone VH. Mitochondrial alterations In cisplatin-induced acute renal failure. Am J Physiol 1986 250 F991-8. Brady HR, Kone BC, StronIskI ME, Zeldel ML, Glebisch G, Gullans SR. Mitochondrial Injury an early event In cisplatin-toxicity to renal proximal tubules. Am J Physiol 1990 258 FI 181-7. 

Fowler BA, Akkerman M.The role of Ca++ in cadmium-induced renal tubular cell injury. In Cadmium in the human environment toxicity and carcinogenicity. Nordberg G, Elerber R, Alessio E (editors). International Agency for Research on Cancer (lARC) Scientific Publications, Vol 118, Lyon 1992 p. 271-277. 

One of the unique features of BLM is its lack of significant hepatic, renal, and bone marrow toxicities, undesired effects of many anticancer drugs. Two drawbacks are the tumor resistance and the BLM-induced pulmonary toxicity. Both effects are related to the level of BLM hydrolase, a protease that binds to DNA and inactivates BLM by hydrolyzing the /3-alanine carboxamide moiety (14, 15). Cells with high levels of BLM hydrolase are resistant to bleomycin, whereas lungs are sensitive to BLM-induced tissue injuries because of low levels of this enzyme. The structure of this protease, which binds DNA and is conserved from bacteria to humans, has been solved (16). 

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