Distal nephrotoxicity of cisplatin demonstrated by urinary kallikrein excretion and morphological study in rats

Abstract

The nephrotoxic effect of cisplatin (4 mg/kg body wt, i.p. injection) was specifically evaluated on the distal tubule. We measured both the tissue concentration and the urinary excretion of kallikrein (UKE), a serine protease mainly synthesized and secreted in the distal connecting tubular cells. In a parallel morphological study, we evaluated the tissue lesions. On the basis of UKE, the three distinct phases of nephrotoxicity were observed. The induction phase, 1 day after cisplatin injection, was associated with a transient increase in UKE. During the maintenance phase, the kallikrein concentration was significantly decreased both in renal cortex and urine for up to 10 days, suggesting an alteration in the biosynthesis with a decrease in the activation of inactive kallikrein. The recovery phase, 21 days after cisplatin injection, was suggested by the incomplete but significant tendency to return towards control values of active UKE. Histological examinations of cisplatin-treated rats showed early lesions of proximal tubules on day 1. The injuries worsened and tubular necrosis was frequently observed on the following days. Distal tubular changes were less marked but vacuolization and desquamation of epithelial cells and swollen and disrupted mitochondria were demonstrated. This study adds new evidence that UKE is a useful and reliable non-invasive index to assess possible nephrotoxic effects in the distal tubule which are also directly visualized by histological lesions.