Repeated intravenous infusion of human apolipoprotein(a) kringle V is associated with reversible dose-dependent acute tubulointerstitial nephritis without affecting glomerular filtration function

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Title
Repeated intravenous infusion of human apolipoprotein(a) kringle V is associated with reversible dose-dependent acute tubulointerstitial nephritis without affecting glomerular filtration function
Author(s)
H J Lee; H K Yu; J H Ahn; Y K Park; Y Yoon; Jang Seong Kim; S J Kim
Bibliographic Citation
Toxicology Letters, vol. 212, no. 3, pp. 298-306
Publication Year
2012
Abstract
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.
Keyword
Angiogenesis inhibitorsApolipoprotein(a)KringlePreclinical drug safety evaluationTubulointerstitial nephritis
ISSN
0378-4274
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.toxlet.2012.05.019
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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