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

Abstract

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 (r_s).

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 (r_s = 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.

Keywords: Chronic kidney disease; Crystalluria; Diagnosis of APRT deficiency; First-morning void urine samples; Kidney stones; Timed urine collections; UPLC-MS/MS assay.

Figure 1.

Scatterplot of 24-hr urinary DHA with (A) sex (p = .03), (B) weight (r_s = 0.36, p = .203), (C) BSA (r_s = 0.36, p = .208), and (D) eGFR (r_s = 0.35, p = .227) in patients with adenine phosphoribosyltransferase deficiency who were not receiving xanthine oxidoreductase inhibitor treatment. Abbreviations: BSA, body surface area; DHA, 2,8-dihydroxyadenine; eGFR, estimated glomerular filtration rate.

Figure 2.

Twenty-four hour urinary DHA excretion in five patients with adenine phosphoribosyltransferase deficiency who were not on xanthine oxidoreductase inhibitor treatment. For each patient, measurements were carried out in urine samples obtained at different time points. Abbreviations: DHA, 2,8-dihydroxyadenine.

Figure 3.

Scatterplot of 24-hr urinary DHA excretion versus DHA/Cr ratio in first-morning void urine samples from patients with adenine phosphoribosyltransferase deficiency who were treated (▴) or not treated (•) with xanthine oxidoreductase inhibitor (r_s = 0.84, p <0.001). *Outliers (+) were excluded from the correlation analysis. Abbreviations: Cr, creatinine; DHA, 2,8-dihydroxyadenine.

Figure 4.

Twenty-four hour urinary DHA excretion versus microscopic DHA crystalluria in patients with adenine phosphoribosyltransferase deficiency who were treated (+) or not treated (○) with xanthine oxidoreductase inhibitor (r_s=0.810, p < 0.001). No patient had 4+ crystalluria. Abbreviations: DHA, 2,8-dihydroxyadenine.