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J Am Soc Nephrol 12:1001-1009, 2001
© 2001 American Society of Nephrology

Diabetes Insipidus in Uricase-Deficient Mice: A Model for Evaluating Therapy with Poly(Ethylene Glycol)-Modified Uricase

SUSAN J. KELLY*, MARIELLE DELNOMDEDIEU{ddagger}, MICHAEL I. OLIVERIO{dagger}, L. DAVID WILLIAMS||, MARK G. P. SAIFER||, MERRY R. SHERMAN||, THOMAS M. COFFMAN{dagger}, G. ALLAN JOHNSON{ddagger} and MICHAEL S. HERSHFIELD*,||

* Division of Rheumatology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
{dagger} Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
{ddagger} Center for In Vivo Microscopy, Department of Radiology, and §Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina
|| Mountain View Pharmaceuticals, Inc., Menlo Park, California.

Correspondence to Dr. Michael S. Hershfield, Box 3049, Duke University Medical Center, Durham, NC 27710. Phone: 919-684-4184; Fax: 919-684-4168; E-mail: msh{at}biochem.duke.edu

Abstract. Uricase-deficient mice develop uric acid nephropathy, with high mortality rates before weaning. Urate excretion was quantitated and renal function was better defined in this study, to facilitate the use of these mice as a model for evaluating poly(ethylene glycol)-modified recombinant mammalian uricases (PEG-uricase) as a potential therapy for gout and uric acid nephropathy. The uric acid/creatinine ratio in the urine of uricase-deficient mice ranges from 10 to >30; on a weight basis, these mice excrete 20- to 40-fold more urate than do human subjects. These mice consistently develop a severe defect in renal concentrating ability, resulting in an approximately sixfold greater urine volume and a fivefold greater fluid requirement, compared with normal mice. This nephrogenic diabetes insipidus leads to dehydration and death of nursing mice but, with adequate water replacement, high urine flow protects adults from progressive renal damage. Treatment of uricase-deficient mice with PEG-uricase markedly reduced urate levels and, when initiated before weaning, preserved the renal architecture (as evaluated by magnetic resonance micros-copy) and prevented the loss of renal concentrating function. PEG-uricase was far more effective and less immunogenic than unmodified uricase. Retention of uricase in most mammals and its loss in humans and some other primates may reflect the evolution of renal function under different environmental conditions. PEG-uricase could provide an effective therapy for uric acid nephropathy and refractory gout in human patients.




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