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The pathology of nephrotoxic injury: a reappraisal
S Rosen1, M Brezis, I Stillman
1Department of Pathology, Harvard Medical School, Boston, Mass.
Abstract:
The class of nephrotoxins which are directly tubulotoxic in animal studies (cis-platinum, gentamicin, and cephaloridine) produce minimal histological changes in the human kidney. Such alterations do not correlate with the degree of organ dysfunction and fall into the broad category of what has been called 'acute tubular necrosis'. Some nephrotoxins (cyclosporine and amphotericin), acutely and chronically diminish renal perfusion, causing injury to renal parenchymal zones known to have limited oxygen a availability (medullary ray and inner stripe). In cyclosporine toxicity, the human and animal models appear equivalent. This is less clear with amphotericin where there appears to be a tubulotoxic component. Other nephrotoxic substances (contrast, nonsteroidal anti-inflammatory drugs) acutely alter renal perfusion, particularly affecting the medulla. In animal models of renal failure induced by these substances, there is an excellent correlation between medullary thick ascending limb injury and renal failure. Documentation of this phenomenon in human biopsies/autopsies is lacking, probably because of the lack of biopsy material and problems in defining medullary injury. Finally, in toxicological screening programs for nephrotoxic substances, there are groups of reactions which cannot be predicted and are thought to be mediated by immune mechanisms, i.e., immune complex glomerular disease, nil disease and interstitial nephritis.
Insights
Directly tubulotoxic drugs cause minimal kidney damage in humans, unlike animal models. Other nephrotoxins impair renal perfusion, with varying effects and correlations in human versus animal studies.
Area of Science:
- Nephrology
- Toxicology
- Pathology
Background:
- Nephrotoxins exhibit varied mechanisms of kidney injury, differing between animal models and human physiology.
- Directly tubulotoxic agents show minimal histological changes in humans, contrasting with animal study findings.
- Some nephrotoxins impact renal perfusion, affecting oxygen-deprived kidney zones.
Purpose of the Study:
- To compare the effects of various nephrotoxins on human and animal kidney models.
- To investigate the correlation between histological changes, organ dysfunction, and specific nephrotoxins.
- To explore the role of immune mechanisms in unpredictable nephrotoxic reactions.
Main Methods:
- Comparative analysis of histological changes in human and animal kidney tissues exposed to nephrotoxins.
- Correlation studies between renal perfusion, medullary injury, and induced renal failure.
- Review of toxicological screening data for immune-mediated nephrotoxic reactions.
Main Results:
- Directly tubulotoxic drugs (cis-platinum, gentamicin, cephaloridine) cause minimal human kidney histological changes, not correlating with dysfunction.
- Cyclosporine and amphotericin reduce renal perfusion, injuring medullary rays and inner stripes; human and animal models align for cyclosporine.
- Contrast agents and NSAIDs alter medullary perfusion; animal models show correlation between medullary thick ascending limb injury and renal failure, but human data is limited.
Conclusions:
- Human kidney responses to certain nephrotoxins differ significantly from animal models, particularly for directly tubulotoxic agents.
- Renal perfusion impairment is a key mechanism for other nephrotoxins, with medullary injury being a critical factor in animal models.
- Immune-mediated reactions remain unpredictable in nephrotoxicological screening, highlighting the complexity of drug-induced kidney injury.