Presentation Authors: Matthew Lindeblad, Chicago, IL, Victoria Bird*, Meekah Chardeton, Ming Yang, Qing-Shan Li, Gainesville, FL, Haifeng Liu, Kangfude, China, People's Republic of, Aaron Cowley, Gainesville, FL
Introduction: Primary Hyperoxaluria is a rare genetic disorder with the hallmark of increased endogenous oxalate production and increased in urine oxalate excretion. This condition can cause calcium oxalate kidney stones and calcium oxalate deposition in kidney tissue which can lead to kidney failure. Our aim was to recreate a purely endogenous increased of oxalate production with remarkable increased urine oxalate to mimic those levels of patients with PH and to test an oxalate decarboxylase enzyme and its effects on reduction of purely endogenous derived urine oxalate.
Methods: A0 is an orally administered recombinant oxalate decarboxylase (OxDC) enzyme from Agrocybe aegerita. To demonstrate its effectiveness a 24-day multiple dose IACUC approved study was conducted in male Gottingen pigs to evaluate the effects of administering A0 on an animal model that mimic PH. Eight Gottingen pigs were administered a zero-oxalate oral diet, consisting of 150 mg of food with 7.5 grams of hydroxyproline (HP) twice a day for 5 days. On day 4 and 5 approximately ~5000 units of A0 were given to pigs about 15 minutes after consuming HP. Urine (24-hour total collection) was collected daily for analysis. Animals were housed individually and placed in metabolic cages on days that required urine collection. Urine was collected in acid to ensure slowed oxalogenesis from ascorbic acid and other oxalate precursors in urine. All animals received the antibiotic oral gentamicin (2 mg/kg) two weeks prior to and throughout the duration of the study, to ensure that the animals were not colonized by Oxalobacter formigenes.
Results: Hyperoxaluria was achieved in the 8 pigs fed a zero oxalate diet, and purely from endogenous production of oxalate from hydroxyproline. A0 dosing significantly decreased urinary oxalate up to 45% of endogenous oxalate (attributed to the HP addition) and 31% total urinary oxalate (>30% urinary oxalate reduction is considered clinically significant in enteric and primary hyperoxaluria). A0's effectiveness has high catalytic efficiency, with a Km between 50-250 uM and a broad active pH profile, pH 1.5-7.5. There were no related effects (body weight, clinical observations, food consumption etc.).
Conclusions: Based on these results, A0 is an agent that can reduce urinary oxalate levels from exclusively endogenous sources by way of enteric elimination.
Source of Funding: NATIONAL INSTITUTES OF HEALTH - NIH RDK089720B