An elevated level of serum uric acid—hyperuricemia, is strongly associated with the development of gout and chronic kidney disease (CKD) which is often accompanied by a significantly reduced glomerular filtration rate (GFR). In the present study, we investigated the extra-renal elimination of uric acid via the intestine in a healthy pig model and the effect of oral uricase therapy on plasma uric acid concentrations in pigs with induced hyperuricemia and CKD. The experiment was conducted on eleven, ten-week-old pigs (n = 11). The porcine model of CKD was developed by performing 9/10 nephrectomy surgery on eight pigs. A stable model of hyperuricemia was established in only five of the eight nephrectomized pigs by frequent injections of uric acid (UA) into the jugular vein. All pigs (three healthy pigs and five CKD pigs) were operated for implantation of jugular vein catheters and the three healthy pigs also had portal vein catheters inserted. Blood uric acid concentrations were measured spectrophotometrically, using the Uric Acid Assay Kit (BioAssay Systems, Hayward, USA). The piglets with CKD received orally administered uricase (treatment) and served as their own controls (without uricase supplementation). Oral uricase therapy significantly decreased plasma uric acid concentrations in pigs with CKD, whereas hyperuricemia was observed in the pigs whilst not being treated with uricase. Urinary uric acid excretion was similar during both the treatment and control periods during the first 8 h and 24 h after UA infusions in the CKD pigs. To demonstrate the elimination of UA via the intestine, the healthy pigs were infused with UA into the jugular vein. The blood collected from the jugular vein represents circulating UA concentrations and the blood collected from the portal vein represents the concentration of UA leaving the intestine. The final (after 2 h) concentration of UA was significantly lower in blood collected from the portal vein compared to that collected from the jugular vein (3.34 vs. 2.43 mg/dL, respectively, p = 0.024). The latter allows us to suggest that UA is eliminated from the blood via the gut tissue.

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Limitations in efficacy and/or tolerance of currently available urate-lowering therapies (ULTs), such as oral xanthine oxidase inhibitors, uricosurics, and intravenous uricase agents contribute to the development of refractory gout. Renal excretion is the major route of uric acid elimination, but the intestinal tract plays an increasingly recognized role in urate homeostasis, particularly in chronic kidney disease (CKD) in which the renal elimination of urate is impaired. We targeted intestinal degradation of urate in vivo with ALLN-346, an orally administered, engineered urate oxidase, optimized for proteolytic stability, and activity in the gut. We tested ALLN-346 in uricase/urate oxidase deficient mice (URKO mice) with severe hyperuricemia, hyperuricosuria, and uric acid crystalline obstructive nephropathy. A total of 55 male and female URKO mice were used in the two consecutive studies. These seminal, proof-of-concept studies aimed to explore both short- (7-day) and long-term (19-day) effects of ALLN-346 on the reduction of plasma and urine urate. In both the 7- and 19-day studies, ALLN-346 oral therapy resulted in the normalization of urine uric acid excretion and a significant reduction of hyperuricemia by 44 and 28% when therapy was given with food over 24 h or was limited for up to 6 h, respectively. Fractional excretion of uric acid (FEUA) was normalized with ALLN-346 therapy. Oral enzyme therapy with engineered urate oxidase (ALLN-346) designed to degrade urate in the intestinal tract has the potential to reduce hyperuricemia and the renal burden of filtered urate in patients with hyperuricemia and gout with and without CKD.

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