Diabetes insipidus in uricase-deficient mice: A model for evaluating therapy with poly(ethylene glycol)-modified uricase

Uricase-deficient mice develop uric acid nephropathy, with high mortality r ates before weaning. Urate excretion was quantitated and renal function was better defined in this study, to facilitate the use of these mice as a mod el for evaluating poly(ethylene glycol)-modified recombinant mammalian uric ases (PEG-uricase) as a potential therapy for gout and uric acid nephropath y. The uric acid/creatinine ratio in the urine of uricase-deficient mice ra nges from 10 to >30; on a weight basis, these mice excrete 20- to 40-fold m ore urate than do human subjects. These mice consistently develop a severe defect in renal concentrating ability, resulting in an approximately sixfol d greater urine volume and a fivefold greater fluid requirement, compared w ith normal mice. This nephrogenic diabetes insipidus leads to dehydration a nd death of nursing mice but, with adequate water replacement, high urine f low protects adults from progressive renal damage. Treatment of uricase-def icient mice with PEG-uricase markedly reduced urate levels and, when initia ted before weaning, preserved the renal architecture (as evaluated by magne tic resonance microscopy) and prevented the loss of renal concentrating fun ction. PEG-uricase was far more effective and less immunogenic than unmodif ied uricase. Retention of uricase in most mammals and its loss in humans an d some other primates may reflect the evolution of renal function under dif ferent environmental conditions. PEG-uricase could provide an effective the rapy for uric acid nephropathy and refractory gout in human patients.