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

Uricase-deficient mice develop uric acid nephropa- thy, 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 mam- malian 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 approxi- mately 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 con- ditions. PEG-uricase could provide an effective therapy for uric acid nephropathy and refractory gout in human patients. Urate oxidase (uricase, EC 1.7.3.4), an enzyme found in liver peroxisomes of most mammalian species, converts uric acid to a more soluble and easily excreted compound, i.e., allantoin. However, the uricase gene (Uox) has undergone mutational silencing during the evolution of humans, hominoid apes, and some New World monkeys (1,2). A selective evolutionary advantage resulting from the loss of uricase has been postu- lated (3,4), but disadvantages resulting from the low solubility of urate include a predisposition to gouty arthritis and to uric acid renal stones (5). During chemotherapy to treat leukemia or lymphoma, a marked increase in the excretion of uric acid derived from the nucleic acids of malignant cells can obstruct renal tubules, causing acute renal failure ("tumor lysis syn- drome") (6 - 8). Uric acid nephropathy and gout are also com- plications of the overproduction or impaired excretion of urate in patients with the inherited disorders hypoxanthine-guanine phosphoribosyltransferase deficiency, phosphoribosylpyro-