Saline is as effective as nitrogen scavengers for treatment of hyperammonemia

G Van Straten,I M Van Geijlswijk,M G M De Sain-Van Der Velden,J Rothuizen,R P Favier,H Fieten,M Van Der Ham,N M Verhoeven-Duif,N E Holwerda-Loof,B Spee,S J Mesu

doi:10.1038/s41598-017-12686-9

Abstract

Urea cycle enzyme deficiency (UCED) patients with hyperammonemia are treated with sodium benzoate (SB) and sodium phenylacetate (SPA) to induce alternative pathways of nitrogen excretion. The suggested guidelines supporting their use in the management of hyperammonemia are primarily based on non-analytic studies such as case reports and case series. Canine congenital portosystemic shunting (CPSS) is a naturally occurring model for hyperammonemia. Here, we performed cross-over, randomized, placebo-controlled studies in healthy dogs to assess safety and pharmacokinetics of SB and SPA (phase I). As follow-up safety and efficacy of SB was evaluated in CPSS-dogs with hyperammonemia (phase II). Pharmacokinetics of SB and SPA were comparable to those reported in humans. Treatment with SB and SPA was safe and both nitrogen scavengers were converted into their respective metabolites hippuric acid and phenylacetylglutamine or phenylacetylglycine, with a preference for phenylacetylglycine. In CPSS-dogs, treatment with SB resulted in the same effect on plasma ammonia as the control treatment (i.e. saline infusion) suggesting that the decrease is a result of volume expansion and/or forced diuresis rather than increased production of nitrogenous waste. Consequentially, treatment of hyperammonemia justifies additional/placebo-controlled trials in human medicine.

Highlights

Hyperammonemia is a dangerous condition that can lead to hepatic encephalopathy (HE) and in severe cases to coma and death[1,2,3]
We assessed the potential of sodium benzoate (SB) and sodium phenylacetate (SPA) to reduce ammonia concentrations in a canine model of hyperammonemia
Due to the similarities of ammonia metabolism, dogs are considered a valid model for hyperammonemia in man[29,31]

Summary

Introduction

Hyperammonemia is a dangerous condition that can lead to hepatic encephalopathy (HE) and in severe cases to coma and death[1,2,3]. Benzoate conjugates with glycine (catalysed by glycine N-benzoyltransferase) to form hippuric acid (HA), and phenylacetate conjugates with glutamine (catalysed by glutamine N-phenylacetyl transferase) to form phenylacetylglutamine (PAG) (Fig. 1) The latter is reported to occur only in humans and higher primates. HA, PAGL and PAG are excreted by the kidneys removing one (HA and PAGL) and two (PAG) moles of waste nitrogen for each mole of benzoate and phenylacetate, respectively[14,15], (Fig. 1) Both SB and SPA have been used therapeutically for many years, we still lack a high level of evidence (such as systematic reviews of randomized controlled trials (RCTs)) supporting the efficacy of these treatments in humans and animals. Clinical symptoms of hyperammonemia in dogs (e.g. depression, ataxia, convulsions and coma) are highly similar to those seen in humans

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