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Abstract: FR-PO530

Effect of Alanine Supplementation on Oxalate Synthesis

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Fargue, Sonia, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Holmes, Ross P., UAB, Birmingham, Alabama, United States
  • Knight, John, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Alanine:glyoxylate aminotransferase (AGT) is the enzyme deficient in type 1 primary hyperoxaluria, which are a group of severe inherited kidney stone disorders characterized by an excessive endogenous synthesis of oxalate. The high Km of AGT for alanine (30 mM) and the lower level of alanine in human plasma (200-600 μM) suggest that AGT metabolic function, and therefore oxalate synthesis, could be improved by alanine supplementation. In support of this hypothesis, cells expressing normal or pathogenic variants of AGT and supplemented with L-alanine, have decreased synthesis of oxalate when incubated with an oxalate precursor, glycolate. In order to test whether L-alanine could improve AGT metabolic efficiency in vivo, we investigated the effect of L-alanine supplementation on the urinary excretion of oxalate in normal mice and mice deficient in AGT or Glyoxylate reductase (GR, deficient in primary hyperoxaluria type 2).

Methods

Wt, Gr Ko and Agt Ko mice were fed a low oxalate diet. Three 24 hr urines were collected in metabolic cages at baseline and after 1 week of equilibration with the low oxalate diet supplemented with 5-10% alanine. Plasma and liver alanine were measured by high-pressure liquid chromatography after extraction of the tissues. Urine oxalate was measured by ion chromatography coupled with mass spectrometry, urine creatinine was measured on a chemical analyzer. Statistical analysis was done with Student’s paired t-test.

Results

Urinary oxalate was higher in Gr and Agt Ko compared with Wt mice at baseline (152 ±35, 215 ± 13 compared with 48 ± 5 μg oxalate/day, in GR KO, Agt Ko and Wt, respectively, p<0.005). Supplementation with L-alanine in the diet resulted in a 20-30% decrease in urinary oxalate in both Gr Ko and Wt animals (106 ± 20 and 36 ± 2 μg oxalate/day after supplementation, p<0.002 and p<0.001, respectively). There was no significant change in urinary excretion of oxalate in Agt Ko mice.

Conclusion

The urinary excretion of oxalate was decreased by dietary L-alanine supplementation in Wt and Gr Ko mice, which express functional Agt. These results suggest that L-alanine could prove useful as an adjunct therapy in PH2 and PH3, for which no specific treatment is currently available, and potentially idiopathic hyperoxaluria.

Funding

  • NIDDK Support