Urinary 2,8-dihydroxyadenine excretion in patients with adenine phosphoribosyltransferase deficiency, carriers and healthy control subjects.

BACKGROUND: Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder of adenine metabolism that results in excessive urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to kidney stones and chronic kidney disease. The purpose of this study was to assess urinary DHA excretion in patients with APRT deficiency, heterozygotes and healthy controls, using a recently developed ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) assay. METHODS: Patients enrolled in the APRT Deficiency Registry and Biobank of the Rare Kidney Stone Consortium (http://www.rarekidneystones.org/) who had provided 24-h and first-morning void urine samples for DHA measurement were eligible for the study. Heterozygotes and healthy individuals served as controls. Wilcoxon-Mann-Whitney test was used to compare 24-h urinary DHA excretion between groups. Associations were examined using Spearman's correlation coefficient (rs). RESULTS: The median (range) 24-h urinary DHA excretion was 138 (64-292) mg/24 h and the DHA-to-creatinine (DHA/Cr) ratio in the first-morning void samples was 13 (4-37) mg/mmol in APRT deficiency patients who were not receiving xanthine oxidoreductase inhibitor therapy. The 24-h DHA excretion was highly correlated with the DHA/Cr ratio in first-morning void urine samples (rs = 0.84, p < .001). DHA was detected in all urine samples from untreated patients but not in any specimens from heterozygotes and healthy controls. CONCLUSIONS: High urinary DHA excretion was observed in patients with APRT deficiency, while urine DHA was undetectable in heterozygotes and healthy controls. Our results suggest that the UPLC-MS/MS assay can be used for diagnosis of APRT deficiency.

Comparison of the effect of allopurinol and febuxostat on urinary 2,8-dihydroxyadenine excretion in patients with Adenine phosphoribosyltransferase deficiency (APRTd): A clinical trial.

INTRODUCTION: Adenine phosphoribosyltransferase (APRT) deficiency is a rare, but significant, cause of kidney stones and progressive chronic kidney disease. The optimal treatment has not been established. The purpose of this pilot study was to compare the effect of the xanthine oxidoreductase inhibitors allopurinol and febuxostat on urinary 2,8-dihydroxyadenine (DHA) excretion in APRT deficiency patients. MATERIALS AND METHODS: Patients listed in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, currently receiving allopurinol therapy, were invited to participate. The trial endpoint was the 24-h urinary DHA excretion following treatment with allopurinol (400mg/day) and febuxostat (80mg/day). Urinary DHA was measured using a novel ultra-performance liquid chromatography - electrospray tandem mass spectrometry assay. RESULTS: Eight of the 10 patients invited completed the study. The median (range) 24-h urinary DHA excretion was 116 (75-289) mg at baseline, and 45 (13-112) mg after 14days of allopurinol therapy (P=0.036). At the end of the febuxostat treatment period, 4 patients had urinary DHA below detectable limits (<20ng/mL) compared with none of the participants following allopurinol treatment (P=0.036). The other 4 participants had a median 24-h urinary DHA excretion of 13.2 (10.0-13.4) mg at the completion of febuxostat therapy (P=0.036). CONCLUSION: Urinary DHA excretion in APRT deficiency patients decreased with conventional doses of both allopurinol and febuxostat. Febuxostat was, however, significantly more efficacious than allopurinol in reducing DHA excretion in the prescribed doses. This finding, which may translate into improved outcomes of patients with APRT deficiency, should be confirmed in a larger sample.