Nitrogen scavengers (e.g., sodium benzoate, sodium phenylbutyrate, and glycerol phenylbutyrate) play a critical role in stabilizing biochemical markers in individuals with UCDs (F.5151, F.5334, F.5717, F.7183). Their use is closely linked to improvements in protein tolerance and metabolic control across UCD phenotypes. Several case reports describe how nitrogen scavengers support higher protein intake while maintaining metabolic stability. In pediatric OTC, sodium benzoate increased protein intake from 1.5 g/kg/day to 2 g/kg/day (F.5561, F.5655). In a 10-month-old with CPS, sodium benzoate combined with sodium phenylacetate nearly doubled protein tolerance (from ~1 g/kg/day to 1.75–2 g/kg/day) and improved growth (F.5982). Among adults, sodium phenylbutyrate increased protein tolerance from 40 g/day to 55 g/day in late-onset OTC (F.4722) and improved metabolic stability in ARG, increasing protein tolerance from 0.16-0.35 g/kg/day to 0.5-0.6 g/kg/day (F.6061). Another ARG case from 1984 showed that sodium benzoate with an arginine-restricted diet improved ammonia control and allowed a less restricted diet (F.6987). Sodium benzoate has also been used to buffer periods of higher protein intake in a 10-year-old male with ARG who was not tracking protein intake (F.5308).

Expert opinion from 2007 advised increasing nitrogen scavenger dosing when protein tolerance is below target or metabolic control is suboptimal (e.g., abnormal plasma amino acids) (F.7801). Similarly, a 2019 survey of 66 clinicians found 68% agreed/strongly agreed that they prescribed scavengers to increase protein intake, although 13% disagreed/strongly disagreed (F.4579). Effective scavenger and protein titration requires coordination between the metabolic provider and dietitian, along with monitoring of ammonia, plasma amino acids, and dietary intake (F.7801).

Nitrogen scavengers are typically prescribed alongside protein restriction as part of UCD management. The benefits of this multipronged approach are also reflected in clinical case studies, such as a 1991 case report, where adding sodium benzoate to a low-protein diet (0.8 g/kg/day) led to lower ammonia concentrations, improved psychomotor development, and better growth outcomes in a pediatric OTC heterozygote (F.7960). However, there are circumstances in which scavengers may be used without protein restriction. For example, in a 2019 survey of 66 clinicians, 70% of physicians agreed/strongly agreed that long-term nitrogen scavenger use may be indicated in asymptomatic female OTC carriers (F.4579).

While nitrogen scavengers may allow for more flexible dietary management, their primary role remains in conjunction with a low protein diet to improve ammonia control.

Delphi 1 Results

There was strong agreement (96%) that, in severe UCD, nitrogen scavengers should be considered whether or not the individual is prescribed a low protein diet. However, in mild UCD, only medical providers agreed (84%) that nitrogen scavengers should be considered in individuals who are prescribed a low protein diet; while almost half of dietitians indicated they neither agreed nor disagreed. Additionally, few agreed with considering nitrogen scavengers for individuals with mild UCD who were NOT prescribed a low protein diet.

Regarding starting or adjusting the dose of nitrogen scavengers, there was strong consensus (91%) that it should be considered when protein intake is stable but plasma glutamine concentration is high (>900 µmol/L) on two consecutive tests. However, agreement fell just short of consensus for the following scenarios: 1) individual desires more liberal diet (79%), 2) individual exhibits suboptimal growth (79%), and 3) individual requires EAA to meet protein needs (75%). Only 52% of providers agreed that trialing a combination of nitrogen scavengers (e.g., phenylbutyrate + sodium benzoate) for dietary optimization was worthwhile.

In an individual established on a low protein diet with nitrogen scavengers and glutamine <700 µmol/L on two consecutive tests, there was strong consensus (91%) that it is appropriate to trial an increased protein goal (from intact protein and/or EAA).

Delphi 2 Results

There was unanimous agreement that close coordination between metabolic dietitians and medical providers is essential to individualize scavenger use and titrate protein intake.

Consensus (83%) supported initiating or increasing the dose of nitrogen scavenger when higher protein tolerance is desired with 100% agreement among providers.

There was also strong agreement (91%) to first consider initiating a nitrogen scavenger in individuals on an unrestricted diet who consume less protein than the typical American diet.

Sodium phenylbutyrate therapy has been associated with reductions in plasma BCAA concentrations (F.6122, F.6123), which may have metabolic consequences in UCDs. A prospective study of 11 individuals with UCDs found that plasma BCAA concentrations, but not other EAAs, were lower in those treated with phenylbutyrate/benzoate compared to controls and asymptomatic OTC heterozygotes (F.7873, F.7874). This finding was confirmed in a large (n=553) cross-sectional study showing sodium phenylbutyrate use was negatively associated with plasma BCAA after controlling for potential confounding variables (F.6123). The depletion of plasma BCAAs could contribute to negative nitrogen balance, impaired protein synthesis, and an increased risk of metabolic decompensation (F.7873). Furthermore, evaluation of registry data from 311 individuals with UCDs showed height z-score was positively associated with plasma concentrations of leucine in CPS, OTC, and HHH syndrome and valine in CIT-I and ASA (F.7964). In contrast, pooled pediatric data (F.4703) and an open-label long-term study (n=88) of both children and adults (F.5150) treated with glycerol phenylbutyrate demonstrated that mean plasma BCAA and other EAA concentrations remained within normal limits throughout treatment. Routine monitoring of plasma BCAAs remains important for individuals with UCDs, particularly those on sodium phenylbutyrate therapy, to prevent catabolism and ensure metabolic stability (F.6122, F.6123).

This topic was not included in the Delphi consensus process.

For individuals with CPS, case studies suggest that carglumic acid may stimulate residual carbamoyl-phosphate synthetase activity, decreasing ammonia and allowing for increased protein intake (F.5156, F.7070). A 1996 case report of a 3-year-old male with CPS showed that carglumic acid effectively increased protein tolerance from 1.5 g/kg to 3.5 g/kg/day while maintaining stable ammonia concentrations (F.7070). In a 2014 study, four out of five patients with late-onset CPS who were given carglumic acid for three days showed decreased ammonia (F.5156). Additionally, a 2022 retrospective study in Korea found that carglumic acid was highly effective in reducing ammonia in one adult with late-onset CPS, though its effect on protein tolerance was not evaluated (F.5548). Individuals with CPS1 mutations with higher residual enzyme activity (e.g., p.Glu1034Gly) may respond better than those with severe mutations (e.g., p.Met792Ile) (F.5548). A trial of carglumic acid is recommended in individuals with partial CPS (F.5156).

Delphi 1 and 2 Results

There was not consensus regarding the use of carglumic acid to improve protein tolerance in individuals with CPS, thus suggesting a potential area for education and research.

Nominal Group

There was unanimous agreement among the eight nominal group participants to consider use of carglumic acid to improve protein tolerance in individuals with CPS.

The aim of L-citrulline supplementation is to ensure adequate arginine can be produced. L-citrulline supplementation is preferred in CPS and OTC as it bypasses first pass metabolism of the liver and is converted to arginine in the kidney, facilitating nitrogen excretion. Older management review articles (1996-2005) recommended L-citrulline supplementation at approximately 170 mg/kg/day for CPS and OTC (F.4691, F.4662, F.4707) with 2019 European guidelines including a range of 100-200 mg L-citrulline/kg/day (maximum of 6 g/day) (F.7963). Standards of practice from one metabolic center recommend starting L-citrulline between 100-300 mg/kg with a goal of 150-170 mg/kg to achieve normal plasma arginine concentrations (G.187).

A 2004 expert opinion suggested that divided doses of L-citrulline (total of 170 mg/kg/day) often result in low plasma arginine concentrations, which may require additional L-arginine supplementation to optimize metabolic control (F.6338). In contrast, findings from a 2017 study of 43 individuals with OTC and CPS suggested that L-citrulline alone (average starting dose 165.3 ± 28.6 mg/kg/day) may be sufficient to support arginine needs (F.6200). Consistent with these findings, analysis of 361 individuals with UCDs in the E-IMD registry showed that L-citrulline supplementation in CPS, OTC, and HHH resulted in significantly higher plasma arginine concentrations compared with selective L-arginine or no supplementation, supporting the preferential use of L-citrulline in these disorders (F.7965). The 2019 European guidelines similarly reported concomitant L-arginine supplementation is generally not required with L-citrulline supplementation (F.7963).

Delphi 1 Results

There was strong consensus (96% and 91%, respectively) that well individuals with severe UCD should be proactively supplemented with L-citrulline or L-arginine to maintain plasma concentrations within the normal range and well individuals with mild UCD should be supplemented if/when plasma concentrations fall below norms.

Arginine is a conditionally essential amino acid in all UCDs except ARG and is necessary to maintain nitrogen balance, prevent hypoargininemia, and facilitate waste nitrogen excretion. Case studies/series and retrospective reviews consistently support the role of arginine in UCD metabolic management, with improved metabolic control, growth, and neurocognitive outcomes when used appropriately in conjunction with protein restriction and nitrogen scavengers (F.4893, F.5334, F.5794, F.5946, F.6423, F.7139, F.7941). L-arginine supplementation is contraindicated in ARG (F.7963).

The overall goal of L-arginine supplementation is to maintain plasma arginine concentrations in the normal range or below twice the upper limit of normal in CIT-I and ASA (F.4662) while preventing hyperammonemic crises and supporting optimal growth and development. Typical dosing varies, with earlier publications (1983-2001) reporting ranges of 400-700 mg/kg/day for CIT-I and ASA (F.4691, F.4662, F.4707, F.5334), while the 2019 European guidelines recommend 100-300 mg/kg/day for children under 20 kg and 2.5-6 g/m²/day for those over 20 kg, noting that higher doses may be necessary in some cases (F.7963).

Long-term management requires individualized adjustments based on plasma amino acid concentrations and clinical response, as excessive arginine can lead to hyperargininemia and associated complications, including spasticity and hepatotoxicity (F.7802). In 2012, 12 individuals with ASA were randomized to receive high dose L-arginine (500 mg/kg/d) or low dose L-arginine (100 mg/kg/d) with phenylbutyrate for one week (F.7973). While both treatment arms were effective in maintaining nitrogen balance, the high dose arm had significantly higher plasma argininosuccinic acid (ASA) and aspartate aminotransferase (AST). Thus, a lower L-arginine dose paired with a nitrogen scavenger could be considered for individuals with existing hepatic disease (F.7973).

For individuals with mild or late-onset CIT-I and ASA, metabolic control may be maintained with reduced L-arginine doses, and in some cases without supplementation (F.5126, F.6132, F.7963). In a 2010 study of late-onset ASA, oral L-arginine supplementation at 400-700 mg/kg/day during early childhood supported normal growth and metabolic control, with some individuals later requiring only low-dose supplementation of 25-150 mg/kg/day (F.6132). A 2009 retrospective review similarly reported effective use of lower L-arginine doses (25-50 mg/kg/day) in mild or late-onset ASA (F.5126). In addition, doses of 150-200 mg/kg/day were successfully used in an adolescent with late-onset CIT-I in conjunction with a low-protein diet and nitrogen scavengers (F.6804).

Delphi 1 results

There was strong consensus (96% and 91%, respectively) that well individuals with severe UCD should be proactively supplemented with L-citrulline or L-arginine to maintain plasma concentrations within the normal range and well individuals with mild UCD should be supplemented if/when plasma concentrations fall below norms.

Delphi 2 Results

There was 83% agreement to supplement individuals with CIT-I and ASA with L-arginine at approximately 100-300 mg/kg/day for those under 20 kg or 2.5-6 g/m²/day for individuals over 20 kg.

There was unanimous agreement among medical providers to using lower doses of L-arginine in individuals with CIT-I and ASA who have hepatic dysfunction or mild/late-onset disease. However, it did not reach consensus overall with several metabolic dietitians noting that amino acid dosing is determined by the medical provider in their clinic.