Correlation of Plasma and Urine 2,8‐Dihydroxyadenine and Adenine and Clinical Characteristics in Individuals With Adenine Phosphoribosyltransferase Deficiency

Adenine phosphoribosyltransferase (APRT) deficiency is a rare, autosomal recessive disorder characterized by urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to kidney stones and chronic kidney disease. Treatment with the xanthine oxidoreductase (XOR) inhibitors allopurinol and febuxostat reduces DHA production. DHA and adenine were measured in 122 paired plasma and urine samples from 26 individuals with confirmed APRT deficiency, using ultra-performance liquid chromatography-tandem mass spectrometry assays. The relationship between plasma DHA and adenine concentrations, urine DHA-to-creatinine (DHA/Cr) and adenine-to-creatinine (adenine/Cr) ratios, and age and estimated glomerular filtration rate (eGFR) was evaluated in a subset of 87 paired plasma and urine samples from 23 individuals using Spearman's rank correlation. Allopurinol and febuxostat treatment reduced plasma DHA, with the median (range) concentration decreasing from 249 (123-1315) ng/mL in untreated individuals to below the limit of detection in those receiving higher doses. Plasma adenine increased during XOR inhibitor treatment. In untreated individuals, a strong negative correlation was observed between plasma DHA and eGFR (r_s = -0.74, p < 0.0001). Plasma DHA correlated with urine DHA/Cr ratio in individuals treated with allopurinol or febuxostat (r_s = 0.65, p < 0.0001), while no significant correlation was observed in untreated individuals (r_s = -0.26, p = 0.14). Treatment with XOR inhibitors effectively reduces the plasma concentration and urinary excretion of DHA. The strong correlation between plasma DHA and eGFR, combined with the lack of correlation between plasma DHA and urine DHA/Cr ratio in untreated individuals, suggests that plasma DHA may be a more reliable marker of systemic DHA burden.