Repeated intravenous infusion of human apolipoprotein(a) kringle V is associated with reversible dose-dependent acute tubulointerstitial nephritis without affecting glomerular filtration function.
Because anti-angiogenic agents have shown various toxicities in clinical applications, the determination of their toxicities and their reversibility is important in the design of clinical trials. This study was performed to investigate the potential toxicities of an angiogenesis inhibitor, apolipoprotein(a) (Apo(a)) kringle V (rhLK8) in rats. Rats administered an intravenous (IV) bolus injection of rhLK8 (200 mg/kg) for 7 days showed significant increases in serum blood urea nitrogen (BUN), creatinine and the BUN/creatinine ratio, which was compatible with acute tubulointerstitial nephritis (TIN) in pathological examination. Because anti-angiogenic therapies are usually based on long-term treatment strategies, rats were administered 200 mg/kg/day of rhLK8 by intravenous infusion for 28 days. Rats receiving 200 mg/kg of rhLK8 showed abnormal serological and histologic findings, but their levels returned to within normal ranges 2 weeks after the cessation of administration. The creatinine clearance rate (CCr) was not affected by rhLK8 treatment. Collectively, our data indicate that the intravenous infusion of rhLK8 at therapeutic doses may induce renal toxicities, such as acute TIN, but these toxicities are clinically tolerable and reversible with close monitoring and a recovery period.
Cancer Biology Team, Mogam Biotechnology Research Institute, 341 Bojeong-dong, Giheung-gu, Yongin 446-799, Republic of Korea.
Ho-Jeong
HJ
Lee
Hyun-Kyung
HK
Yu
Jin-Hyung
JH
Ahn
Yong-Keun
YK
Park
Yeup
Y
Yoon
Jang-Seong
JS
Kim
Sun-Jin
SJ
Kim
D000208:Acute Disease; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001054:Apolipoproteins A / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D001806:Blood Urea Nitrogen; D004305:Dose-Response Relationship, Drug; D060730:Glomerular Filtration Barrier; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D018675:Toxicity Tests; D015430:Weight Gain / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D001054:Apolipoproteins A; C574732:LK8 peptide; D010446:Peptide Fragments