Journal
TRANSPLANTATION
Volume 85, Issue 9, Pages 1253-1260Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/TP.0b013e31816de49e
Keywords
primary hyperoxaluria type-1; preparative irradiation; nephrocalcinosis; adenovirus; hepatic growth factor
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Funding
- NCI NIH HHS [R33 CA121051, R21 CA121051] Funding Source: Medline
- NIDDK NIH HHS [R01 DK39137, P30 DK41296, R01 DK064670, R01 DK46057] Funding Source: Medline
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Background. Primary hyperoxaluria type-1 (PH1) is an autosomal recessive disease characterized by excessive oxalate production by hepatocytes caused by the deficiency of peroxisomal alanine-glyoxylate aminotransferase (AGT) activity. Persistent hyperoxaluria causes nephrocalcitiosis and urolithiasis, leading to renal failure, followed by tissue oxalosis with life-threatening complications. Combined liver-kidney transplantation is the only definitive treatment of PHI. Hepatocyte transplantation, which is much less invasive, could have offered an attractive alternative. However, because the AGT-deficient hepatocytes overproduce oxalate, a large fraction of the mutant host hepatocytes must be replaced by AGT-competent cells, which is beyond the capacity of current hepatocyte transplantation procedures. Here, we have evaluated a preparative irradiation-based method of liver repopulation in an Agxt-deleted mouse model of PHI (Agxt(-/-)). Materials and Methods. Hepatocytes (10(6) viable cells) isolated from congeneic mice ([ROSA]26 C57BL/6J) expressing Escherichia coli beta-galactosidase were transplanted intoAgxt(-/-) mice by intrasplenic injection. The preparative regimen consisted of X-irradiation of the host liver and Mitotic Stimulation of the hepatocytes by adenovector-based expression of hepatocyte growth factor. Results. The procedure resulted in progressive replacement of the mutant host hepatocytes with the AGT-competent hepatocytes, leading to correction of urinary oxalate excretion. Oral ethylene glycol challenge (0.7% for 1 week) resulted in nephrocalcinosis and microlithiasis in untreated Agxt(-/-) mice, but not in the mice after hepatic repopulation. Conclusion. The results indicate that hepatocyte transplantation after appropriate preparative regimens may permit sufficient repopulation of the liver to ameliorate hyperoxaluria, and therefore should be evaluated further as a potential treatment of PHI.
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