Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele

Pyridoxine (VB6) response in type I primary hyperoxaluria (PHI) is variable, with nearly equal numbers of patients showing partial to complete reductions in oxaluria, and resistance. Because high urine oxalate concentrations cause stones and renal injury, reduction in urine oxalate excretion is deemed favorable. Mechanisms of VB6 action on hepatic alanine:glyoxylate aminotransferase (AGT), the deficient enzyme in PHI, and VB6 dose response have not been well-characterized.

Sequencing or restriction site-generating polymerase chain reaction (PCR) was used for c.508 genotyping in 23 PHI patients. Pre- and post-VB6 24-hour urine oxalate excretion and VB6 dose were ascertained by retrospective chart review.

There were six c.508 G>A homozygotes (AA), eight heterozygotes (GA), and nine patients lacking this change (GG). Pre-VB6 urine oxalate excretion was 152 +/- 39, 203 +/- 68 and 206 +/- 74 mg/1.73 m(2)/24 hours, respectively, and did not differ [AA vs. GA (P= 0.07); AA vs. GG (P= 0.07); GA vs. GG, (P= 0.47)]. Post-VB6 urine oxalate excretion was normal in AA (pre- vs. post-VB6) (P < 0.001), partially reduced in GA (P < 0.001), and unchanged in GG (P= 0.06). Urine oxalate excretion attenuation was similar for VB6 doses (mg/kg/day) of 1 to 4.9, 5 to 9.9, and 10 to 14.9 in AA (P= 0.41, P= 0.28, and P= 0.11, respectively) and GA (P= 0.42, P= 0.39, and P= 0.30, respectively) during follow-up.

Presence of the c.508 G>A allele confers VB6 response in PHI and VB6 doses of 5 mg/kg/day appear sufficient. c.508 genotyping can be used to predict VB6 response and guide treatment in PHI. [c represents cDNA sequence where nucleotide position +1 corresponds to the adenine (A) of the translation start codon ATG. Equivalent positions based on 5' UTR nucleotide numbering are as follows: c.508 G>A = G630A (Gly170Arg), c.32 C>T = C154T (Pro11Leu), and c.454 T>A = T576A (Phe152Ile)], yields highest residual AGT activity. To test whether VB6 response might be attributable to this allele, we performed c.508 genotyping.