Reversible nephrotoxicity of onconase and effect of lysine pH on renal onconase uptake

Purpose: To examine the histopathology of the kidney in mice following repe ated injections of the antitumor drug onconase, and to determine whether ly sine, which reportedly blocks kidney uptake of other basic proteins, blocks the high renal uptake of onconase. Methods: Mice received repeated intrape ritoneal onconase injections over 3 weeks. Kidneys were examined by light m icroscopy after 1 week, 3 weeks, and 5 weeks (2 weeks after cessation of in jections) and compared to kidneys from animals receiving a similar schedule of PBS injections. Renal uptake of radioiodinated onconase was measured in animals receiving intraperitoneal injections of lysine solutions of acidic and neutral pH given at -30, 0 and +5 min relative to intravenous onconase injection. Renal onconase uptake was also measured in animals made metabol ically acidotic by ingestion of ammonium chloride, arginine chloride or lys ine dihydrochloride from the drinking water. Results: Onconase caused acute moderate multifocal proximal renal tubular necrosis, and this toxicity was reversed by 2 weeks after drug withdrawal. Intraperitoneal injections of l ysine dihydrochloride in PBS (pH 1.5) reduced renal onconase uptake at 15 m in from 67.9 +/- 13.4% to 17.0 +/- 3.8% of the injected dose without affect ing the plasma concentration and also reduced the fraction of degraded onco nase in the urine. However, neutral solutions of lysine dihydrochloride at pH 7.4 or lysine acetate at pH 7.1 were ineffective at blocking renal oncon ase uptake. Furthermore, renal onconase uptake was minimally or not affecte d by a state of metabolic acidosis. Conclusions: Proximal tubular toxicity of onconase was reversible. Renal onconase uptake was blocked by lysine at pH 1.5 but not at neutral pH.