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

Published:December 12, 2017DOI:https://doi.org/10.1016/j.ejim.2017.10.007

      Highlights

      • Both allopurinol and febuxostat effectively reduced urinary DHA excretion in APRTd patients.
      • Febuxostat was significantly more efficacious than allopurinol in the prescribed doses.
      • This finding which may translate into improved outcomes should be confirmed in a larger sample.
      • Allopurinol doses in the range of 600–800 mg daily may be required to control dihydroxyadeninuria.

      Abstract

      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 (400 mg/day) and febuxostat (80 mg/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 14 days of allopurinol therapy (P = 0.036). At the end of the febuxostat treatment period, 4 patients had urinary DHA below detectable limits (<20 ng/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.

      Keywords

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      References

        • Edvardsson V.
        • Palsson R.
        • Olafsson I.
        • Hjaltadottir G.
        • Laxdal T.
        Clinical features and genotype of adenine phosphoribosyltransferase deficiency in Iceland.
        Am J Kidney Dis. 2001; 38: 473-480
        • Edvardsson V.O.
        • Goldfarb D.S.
        • Lieske J.C.
        • Beara-Lasic L.
        • Anglani F.
        • Milliner D.S.
        • et al.
        Hereditary causes of kidney stones and chronic kidney disease.
        Pediatr Nephrol. 2013; 28: 1923-1942
        • Sahota A.
        • Tischfield J.
        • Kamatani N.
        • Simmonds H.
        Adenine phosphoribosyltransferase deficiency and 2,8-dihydroxyadenine lithiasis.
        in: Scrive C.R. Beaudet A.L. Sly W.S. Valle D. Vogelstein B. Childs B. The metabolic and molecular bases of inherited disease. 8 ed. Vol 1. McGraw-Hill, New York, NY2001: 2571-2584
        • Runolfsdottir H.L.
        • Palsson R.
        • Agustsdottir I.M.
        • Indridason O.S.
        • Edvardsson V.O.
        Kidney disease in adenine phosphoribosyltransferase deficiency.
        Am J Kidney Dis. 2016; 67: 431-438
        • Zaidan M.
        • Palsson R.
        • Merieau E.
        • Cornec-Le Gall E.
        • Garstka A.
        • Maggiore U.
        • et al.
        Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.
        Am J Transplant. 2014; 14: 2623-2632
        • Bollee G.
        • Dollinger C.
        • Boutaud L.
        • Guillemot D.
        • Bensman A.
        • Harambat J.
        • et al.
        Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency.
        J Am Soc Nephrol. 2010; 21: 679-688
        • Becker M.A.
        • Schumacher Jr., H.R.
        • Wortmann R.L.
        • MacDonald P.A.
        • Palo W.A.
        • Eustace D.
        • et al.
        Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout.
        Arthritis Rheum. 2005; 52: 916-923
        • Arnadottir M.
        Febuxostat in adenosine phosphoribosyltransferase deficiency.
        Am J Kidney Dis. 2014; 64: 316
        • Thorsteinsdottir M.
        • Thorsteinsdottir U.A.
        • Eiriksson F.F.
        • Runolfsdottir H.L.
        • Agustsdottir I.M.
        • Oddsdottir S.
        • et al.
        Quantitative UPLC-MS/MS assay of urinary 2,8-dihydroxyadenine for diagnosis and management of adenine phosphoribosyltransferase deficiency.
        J Chromatogr B Analyt Technol Biomed Life Sci. 2016; 1036-1037: 170-177
        • Graham S.
        • Day R.O.
        • Wong H.
        • McLachlan A.J.
        • Bergendal L.
        • Miners J.O.
        • et al.
        Pharmacodynamics of oxypurinol after administration of allopurinol to healthy subjects.
        Br J Clin Pharmacol. 1996; 41: 299-304
        • Day R.O.
        • Graham G.G.
        • Hicks M.
        • McLachlan A.J.
        • Stocker S.L.
        • Williams K.M.
        Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol.
        Clin Pharmacokinet. 2007; 46: 623-644
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • Zhang Y.L.
        • Castro 3rd, A.F.
        • Feldman H.I.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Singh J.A.
        • Akhras K.S.
        • Shiozawa A.
        Comparative effectiveness of urate lowering with febuxostat versus allopurinol in gout: analyses from large U.S. managed care cohort.
        Arthritis Res Ther. 2015; 17: 120
        • Becker M.A.
        • Schumacher Jr., H.R.
        • Wortmann R.L.
        • MacDonald P.A.
        • Eustace D.
        • Palo W.A.
        • et al.
        Febuxostat compared with allopurinol in patients with hyperuricemia and gout.
        N Engl J Med. 2005; 353: 2450-2461
        • Massey V.
        • Komai H.
        • Palmer G.
        • Elion G.B.
        On the mechanism of inactivation of xanthine oxidase by allopurinol and other pyrazolo[3,4-d]pyrimidines.
        J Biol Chem. 1970; 245: 2837-2844
        • Komoriya K.
        • Hoshide S.
        • Takeda K.
        • Kobayashi H.
        • Kubo J.
        • Tsuchimoto M.
        • et al.
        Pharmacokinetics and pharmacodynamics of febuxostat (TMX-67), a non-purine selective inhibitor of xanthine oxidase/xanthine dehydrogenase (NPSIXO) in patients with gout and/or hyperuricemia.
        Nucleosides Nucleotides Nucleic Acids. 2004; 23: 1119-1122
        • Harambat J.
        • Bollee G.
        • Daudon M.
        • Ceballos-Picot I.
        • Bensman A.
        Adenine phosphoribosyltransferase deficiency in children.
        Pediatr Nephrol. 2012; 27: 571-579
        • Beara-Lasic L.
        • Pillinger M.H.
        • Goldfarb D.S.
        Advances in the management of gout: critical appraisal of febuxostat in the control of hyperuricemia.
        Int J Nephrol Renovasc Dis. 2010; 3: 1-10