title: Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase.
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.
authors.affiliation: Division of Rheumatology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Kelly
authors.affiliation: Center for In Vivo Microscopy, Department of Radiology, and Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Marielle
authors.initials: M
authors.lastname: Delnomdedieu
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Oliverio
authors.affiliation: Mountain View Pharmaceuticals, Inc., Menlo Park, California.
authors.forename: L David
authors.initials: LD
authors.lastname: Williams
authors.affiliation: Mountain View Pharmaceuticals, Inc., Menlo Park, California.
authors.forename: Mark G P
authors.initials: MGP
authors.lastname: Saifer
authors.affiliation: Mountain View Pharmaceuticals, Inc., Menlo Park, California.
authors.forename: Merry R
authors.initials: MR
authors.lastname: Sherman
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
authors.affiliation: Center for In Vivo Microscopy, Department of Radiology, and Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina.
authors.forename: G Allan
authors.initials: GA
authors.lastname: Johnson
authors.affiliation: Division of Rheumatology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.|Mountain View Pharmaceuticals, Inc., Menlo Park, California.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hershfield
mesh_terms: D000818:Animals; D001834:Body Water / Q000378:metabolism; D003919:Diabetes Insipidus / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006073:Gout / Q000188:drug therapy; D006801:Humans; D007671:Kidney Concentrating Ability; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D014503:Urate Oxidase / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use*; D014527:Uric Acid / Q000652:urine
chemical_list: D011994:Recombinant Proteins; D014527:Uric Acid; D011092:Polyethylene Glycols; D014503:Urate Oxidase; C031545:Pegloticase