Vitamin B6 in primary hyperoxaluria I: first prospective trial after 40 years of practice

Abstract

Background and objectives: Primary hyperoxaluria type I (PH I) is caused by deficiency of the liver-specific enzyme alanine-glyoxylate:aminotransferase (AGT). Many mutations are known to perturb AGT protein folding. Vitamin B6 (B6) is the only specific drug available for treatment. Although B6 has been used for >40 years, controlled data on B6 efficacy are lacking. Therefore, this study investigated the absolute and relative change of urinary oxalate (Uox) excretion under increasing dosages of B6, the first prospective trial to do so.

Design, setting, participants, & measurements: B6 response was studied in 12 patients (7 male patients) with genetically confirmed PH I (3 Gly170Arg homozygous, 5 compound Gly170Arg and/or Phe152Ile heterozygous, and 4 negative for Gly170Arg and/or Phe152Ile mutations) and noncompromised renal function. Efficacy was defined as a 30% relative reduction in Uox excretion. B6 was administered orally starting at 5 mg/kg body weight per day and given in increments of 5 mg/kg every 6 weeks, up to a final dosage of 20 mg/kg per day at week 24. Uox and serum B6 levels were measured every 6 weeks.

Results: Mean relative Uox reduction was 25.5%. Uox declined from 2.09±0.55 (mean±SD) at baseline to 1.52±0.60 mmol/1.73 m(2) per day (P=0.01) at week 24. Serum B6 levels increased from 22.5±8.7 to 1217±776 ng/ml (P<0.001). Six patients showed a ≥30% relative reduction of Uox at week 24.

Conclusion: This first prospective trial confirmed B6 efficacy in 50% of patients (three of three homozygous, one of five heterozygous, and two of four patients negative for the Gly170Arg and/or Phe152Ile mutations). Interestingly, no complete biochemical remission was observed, even in the homozygous Gly170Arg study participants. Future trials are necessary to learn more about genotype-related B6 response and B6 metabolism.

Trial registration: ClinicalTrials.gov NCT01281878.

Figures

Figure 1.

Absolute urinary oxalate(Uox)excretion at study week 0 versus study week 24 among the three different genotype groups (c.508G>A homozygous n=3; c.508G>A and/or c.454T>A compound heterozygous n=5; c.508G>A negative n=4). Shown are medians and 25th and 75th percentiles. Gray circles represent individual study participants.

Figure 2.

Individual relative change in Uox excretion from study week 0 to study week 24 for individual study participants. Response, defined as relative change of ≥30%, is marked as the gray line. Continuous line represents c.508G>A homozygous study participants, dashed line represents c.508G>A and/or c.454T>A compound heterozygous, spotted line represents c.508G>A negative study participants.

Figure 3.

Individual series of serum vitamin B6 levels study weeks 0–24 depending on administered dosage of vitamin B6.r=0.66 (95% confidence interval, 0.48 to 0.78); P<0.001). Responders are depicted as solid lines, and nonresponders are depicted as dashed lines.

Figure 4.

Relationship between relative change of Uox excretion and cumulative serum vitamin B6 levels during study weeks 0–24. Relative change of Uox excretion reduction level in dependence of time-integrated serum vitamin B6 levels (area under the curve) shown for all individual study participants (r=0.26; 95% confidence interval, −0.37 to 0.72); P<0.4). Responders are depicted as solid circles, and nonresponders are depicted as gray circles.