Animal models nephrotoxicity

Animal model Nephrotoxic agent Predominant mechanism of decreased GFR Primary site of injury Reference... 

Imipenem, a carbapenem antimicrobial, also possesses nephrotoxic potential. In animal models, nephrotoxicity is dose dependent and characterized by tubular necrosis. Interestingly, imipenem nephrotoxicity is markedly attenuated by co-administration of cilastatin, an inhibitor of the cytosolic and brush border enzyme dehydropeptidase I (DHP). Although DHP is responsible for hydrolyzing imipenem to inactive metabolites, the major protective effect of cilastatin appears to be due to inhibition of renal imipenem accumulation rather than DHP inhibition. 

A novel approach to the problem of amiaoglycoside nephrotoxicity has been to search for compounds that can inhibit toxicity without compromising efficacy. A number of agents have been reported to reduce amiaoglycoside toxicity ia animal models the most extensively studied of these is sodium polyaspartate (103—107). 

Hypertension is associated with increased TXA2 and decreased PGE2 and PGI2 synthesis in some animal models, eg, the Goldblatt kidney model. It is not known whether these changes are primary contributing factors or secondary responses. Similarly, increased TXA2 formation has been reported in cyclosporine-induced nephrotoxicity, but no causal relationship has been established. 

In an animal model, indinavir nephrotoxicity was potentiated by co-trimoxazole, but nelfinavir alone or in combination with co-trimoxazole was not nephrotoxic (189). 

Combined report on regular dialysis and transplantation in Europe, XIX, 1988. Nephrol Dial Transplant 1989 4(Suppl4) 5-29. Porter GA. Bennett WM, Gilbert DN. Unraveling aminoglycoside nephrotoxicity using animal models. J Clin Pharmacol 1983 23 445-452. 

Ischemic, nephrotoxic, and septic rodent models of acute renal injury were developed to study mechanisms of acute kidney injury. Decreasing renal blood flow is critical in the pathophysiology of AKI in humans. Ischemic and other animal models are used to reproduce the morphological features of human disease. 

Table 3 shows the predominant mechanism of a decrease in GFR in different animal models of nephrotoxic AKI. 

The demonstration of a renal protective effect of salt loading on AmB-induced nephrotoxicity in animal models has provided a rational basis to evaluate this simple intervention in patients. Clinical evidence supporting the ability of sodium loading to attenuate AmB-induced nephrotoxicity is derived from three sources case reports, retrospective studies and prospective studies. 

Tacrolimus causes acute reversible renal dysfunction in renal [661-663,667], hver [290,664-666,679,680], heart [681-683] and pulmonary [684, 685] transplant recipients and in patients with immunologically mediated diseases [686]. Tacrolimus-induced GFR and RBF decrease is associated with an important increase in renal vascular resistance, both in humans and rodents [63,679,687-692]. Calcium channel blockers improved renal function in TAC-treated liver transplant recipients [693] and in animal models of TAC nephrotoxicity [689,694-6%]. Tacrohmus acute nephrotoxicity, similar to CSA, shows normal renal histology or non-specific changes such as isometric cytoplasmic vacuolation in tubular epithelial cells, microcalcification, giant mitochondria and lysosomes, and necrosis and early hyahnosis of individual smooth muscle cells in the afferent arterioles, which revert with drug reduction or discontinuation [697-699]. 

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