Hepatocyte Transplantation in the Dalmatian Dog Model of Hyperuricosuria

Abstract

Hepatocyte transplantation shows promise as a therapy to support liver function. We have previously shown that hepatocytes can be transplanted into prevascularized synthetic polymers in rat and pig models. This study was designed to assess the possibility of correction of a liver metabolic defect in a dog model. The Dalmatian dog is known to have an inborn error of metabolism in the hepatocyte that causes a decrease in the degradation of uric acid into allantoin. This leads to a rise in uric acid levels in blood and urine. Four male Dalmatian dogs 18-28 kg in weight were studied as recipients of normal hepatocytes. Poly vinyl alcohol sponges measuring 250 cm(2) x 5 mm were first implanted between the leaves of the mesentery and the omentum to form prevascularized implantation beds, and an end-to-side portacaval shunt to induce hepatotrophic stimulation was made. After 7 days 1.5 x 10(10) normal hepatocytes obtained from donor beagles receiving cyclosporine immunosuppression were implanted into the prevascularized sponges. Excretion of uric acid in urine decreased from 136.3 +/- 18.1 to 44.1 +/- 20.4 micromol/kg/day (p < 0.05) in these animals at 2 weeks, and continued for 6 weeks. Uric acid levels in serum did not change significantly from 26.77 +/- 10.30 to 39.65 +/- 9.09 micromol/liter (mean +/- SD) 4 weeks after transplantation. Control Dalmatians, which were transplanted with Dalmatian hepatocytes, remained at baseline. Creatinine clearance was unchanged. We conclude that hepatocyte transplantation is possible in this Dalmatian dog model of hyperuricosuria and that urinary excretion of uric acid can be decreased by beagle hepatocyte transplantation delivered in prevascularized synthetic polymer sponges using portacaval shunts as hepatotrophic stimulation.