ReviewCisplatin Nephrotoxicity: A Review
Section snippets
Cisplatin Uptake into Renal Cells
Uptake of cisplatin is mainly through the organic transporter pathway. The kidney accumulates cisplatin to a greater degree than other organs and is the major route for its excretion. The cisplatin concentration in proximal tubular epithelial cells is about 5 times the serum concentration.4 The disproportionate accumulation of cisplatin in kidney tissue contributes to cisplatin-induced nephrotoxicity.5
In the rat, cisplatin excretion occurs predominantly by glomerular filtration and to a lesser
Pathophysiological Effects of Cisplatin Injury
Unbound cisplatin is filtered at the glomerulus (80% of a dose is excreted in 24 hours). Renal blood flow can decrease within 3 hours after cisplatin infusion, and glomerular filtration rate (GFR) falls after the decrease in renal blood flow.49 The mediators responsible for the fall in renal blood flow and GFR have not been determined, and neither calcium channel blockers nor angiotensin converting enzyme inhibitors reverse cisplatin-induced ARF.50 The changes in GFR and renal blood flow probably
Pathological Changes in the Kidney
Cisplatin nephrotoxicity primarily causes tubulo-interstitial lesions. In animal models cisplatin damages the proximal tubules, specifically the S3 segment of the outer medullary stripe. Mitochondrial swelling and nuclear pallor occur in the distal nephron. The glomerulus has no obvious morphologic changes.49., 56., 59. Only a few studies have described the pathological results associated with cisplatin-induced nephrotoxicity in humans.49., 56., 59., 60. The site of injury involves either the
Diagnostic Criteria for Cisplatin Injury
Cisplatin-induced renal injury probably does not have unique diagnostic features. Many patients have changes in glomerular filtration which could be identified by more sensitive tests such as inulin clearance before there are changes in serum creatinine and glomerular filtration measured by creatinine collection. Urinary excretion of a proximal tubular injury markers, such as β-2 microglobulin, N-acetyl-β-D-glucosaminidase, and α1-acid glycoprotein, increase after cisplatin treatment.53 There
Approaches to Prevention
These various approaches are summarized in Table 2.
Treatment of Cisplatin Nephrotoxicity
There is no specific treatment for cisplatin-induced renal dysfunction or injury. These patients need careful attention to hydration and electrolyte treatment. They frequently need magnesium and potassium replacement. Cisplatin and magnesium affect the same sodium and water channels in the outer medulla. Cisplatin induces magnesium depletion, and magnesium deficiency itself may enhance cisplatin nephrotoxicity. Cisplatin treatment often produces extensive gastrointestinal side effects, which
Summary
In this review, we focus on the pathophysiology of toxic renal injury caused by an important chemotherapeutic agent. Critical issues include drug uptake by target cells, drug metabolism within target cells, changes in gene expression, and activation of injury pathways, including oxidative stress, inflammation, and programmed cell death. Since toxins that cause tubular injury share many pathophysiological features with ischemic damage, cisplatin potentially provides an excellent model not only
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