Pathogenetic mechanisms of nephrotoxicity: insights into cyclosporine nephrotoxicity.
Drugs may produce acute renal failure by prerenal, intrarenal and obstructive (postrenal) mechanisms. Prerenal processes usually develop from an imbalance of the normal counterbalancing vasoconstrictor and vasodilatory substances regulating RBF, resulting in a predominant vasoconstrictive state. Intrarenal processes develop from toxic renal tubule epithelial cell injury. The pathogenesis of renal cell injury is a complex interplay among derangements in subcellular membrane functions and mediators of injurious processes. Plasma and subcellular membrane injury and resulting membrane dysfunction appear most important. Cyclosporine has the ability to interact with renal tubular cell membranes in a relatively specific manner and at low concentrations. Despite this interaction, the acute declines in renal excretory function produced by cyclosporine is due predominantly to functional declines in RBF rather than structural derangements in renal tubular cell integrity. Cyclosporine-induced acute renal failure, thus, appears to be due predominantly to prerenal, rather than intrarenal, processes in the experimental animal. Cyclosporine does, however, possess a limited toxic potential to injure renal cortical cells, so that a chronic tubulointerstitial nephropathy may develop with long-term use of this immunosuppressive agent.
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002118:Calcium / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D003524:Cyclosporins / Q000009:adverse effects* / Q000633:toxicity; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005609:Free Radicals; D006801:Humans; D008054:Lipid Peroxides / Q000502:physiology; D008247:Lysosomes / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D010740:Phospholipases / Q000502:physiology; D012078:Renal Artery Obstruction / Q000139:chemically induced
D003524:Cyclosporins; D005609:Free Radicals; D008054:Lipid Peroxides; D010740:Phospholipases; D002118:Calcium