Cell Biology – Immunology – Pathology

Kidney International (2005) 67, 2159–2167; doi:10.1111/j.1523-1755.2005.00321.x

Dendrimer-enhanced MRI as a diagnostic and prognostic biomarker of sepsis-induced acute renal failure in aged mice

JAMES W DEAR, HISATAKA KOBAYASHI, SANG-KYUNG JO, MIKAELA K HOLLY, XUZHEN HU, PETER S T YUEN, MARTIN W BRECHBIEL and ROBERT A STAR

Renal Diagnostics and Therapeutics Unit, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Metabolism Branch and Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Correspondence: Robert A. Star, M.D., Renal Diagnostics and Therapeutics, NIDDK, 10 Center Drive, Building 10, Room 3N108, Bethesda,MD20892–1268. E-mail:Robert_Star@nih.gov

Received 20 December 2004; Accepted 8 November 2004.

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Abstract

Dendrimer-enhanced MRI as a diagnostic and prognostic biomarker of sepsis-induced acute renal failure in aged mice.

Background

 

Acute renal failure (ARF) induced by sepsis has a high mortality. In an aged mouse model of sepsis-induced ARF we have previously shown that renal injury occurs before serum creatinine is elevated. Development of a noninvasive biomarker that could diagnose renal dysfunction early in sepsis and monitor the response to therapy would be very valuable.

Methods

 

We performed magnetic resonance imaging (MRI) with gadolinium-based G4 dendrimer intravenous contrast in a fluid- and antibiotic-treated cecal ligation and puncture (CLP) sepsis model in aged mice. Imaging was also performed in a mouse volume depletion model and in models of ARF induced by ischemia/reperfusion (I/R) and cisplatin.

Results

 

Twenty hours post-CLP, aged mice had a distinct pattern of renal injury using dendrimer-enhanced MRI. This pattern was different from renal injury induced by either cisplatin or I/R. Prerenal azotemia induced by volume depletion was distinguished from sepsis by dendrimer-enhanced MRI. Dendrimer-enhanced MRI detected renal dysfunction 6 hours post-CLP, a time when serum creatinine was still normal. Ethyl pyruvate reversed the renal dysfunction detected by dendrimer-enhanced MRI at 20 hours, but not at 6 hours post-CLP. The appearance of renal dysfunction on dendrimer-enhanced MRI at 6 hours post-CLP predicted the length of survival.

Conclusion

 

Dendrimer-enhanced MRI is a novel biomarker that provides information for the early diagnosis, drug responsiveness, and prognosis of sepsis-induced ARF.

Keywords:

sepsis, MRI, gadolinium, dendrimer, acute renal failure, noninvasive, ethyl pyruvate

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