Doctoral Defense in Pharmacy - Unnur Arna Þorsteinsdóttir

On Thursday, February 27, 2025, Unnur Arna Þorsteinsdóttir will defend her doctoral dissertation at the Faculty of Pharmacy, University of Iceland. The dissertation is titled: "UPLC-MS/MS Assays for Diagnosis of APRT Deficiency and Monitoring of Pharmacotherapy."

The opponents are Dr. Daniel T. Holmes, clinical professor and department head at St. Paul's Hospital in Vancouver, and Dr. Joe M. El-Khoury, associate professor at Yale University School of Medicine.

The supervisor and co-supervisors were Margrét Þorsteinsdóttir, professor, and Runólfur Pálsson, professor. Additionally, the doctoral committee included Viðar Örn Eðvarðsson, professor, Jón Jóhannes Jónsson, professor, and Matthew Lewis, vice president of Bruker Daltonics.

Elvar Örn Viktorsson, lecturer and associate department head of the Faculty of Pharmacy, will chair the ceremony, which will take place in the University of Iceland's Hátíðasalur and will begin at 1:00 PM.

Abstract

Adenine phosphoribosyltransferase (APRT) deficiency is a rare, hereditary disorder of purine metabolism, characterized by renal excretion of the poorly soluble 2,8-dihydroxyadenine (DHA) in large amounts, leading to kidney stone formation and chronic kidney disease (CKD). Treatment with a xanthine oxidoreductase (XOR) inhibitor, allopurinol or febuxostat, reduces urinary DHA excretion, new kidney stone formation and slows CKD progression. There is a need for more reliable quantitative methods for both diagnosis of APRT deficiency and TDM.

The aims of this thesis were to develop, optimize, and validate assays based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for quantification of DHA and adenine in urine and DHA, adenine allopurinol, oxypurinol (active metabolite of allopurinol) and febuxostat in plasma.

Two UPLC-MS/MS assays were successfully developed and validated according to published guidelines, demonstrating adequate accuracy, precision, and stability across the concentration ranges of the analytes.

The clinical application of the assays revealed significant correlations between plasma DHA concentration, estimated glomerular filtration rate (eGFR), and age in patients who were not receiving XOR inhibitor therapy, supporting the value of using plasma DHA as a biomarker for systemic DHA load in APRT deficiency patients with a broad range of kidney function. XOR inhibitor therapy significantly reduced urinary DHA excretion and plasma levels in a dose-dependent manner.

The findings in this thesis provide important insights into the pathophysiology of APRT deficiency and highlight the complementary role of the two assays in diagnosis and pharmacotherapy monitoring.

Together, the plasma and urine assays will facilitate individualized care of patients with APRT deficiency, likely resulting in improved outcomes of this serious disease.

About the doctoral candidate

Unnur Arna Þorsteinsdóttir was born in 1989 in Copenhagen. She graduated from the Natural Sciences Program at Menntaskólinn við Hamrahlíð in 2008. She completed her B.Sc. in Biology at the University of Copenhagen in 2012 and her master’s degree in Cell Biology from the same university in 2015. Unnur began her doctoral studies at the University of Iceland in 2016. The research project received funding from the Icelandic Research Fund and the Eimskip Fund at the University of Iceland. Alongside her doctoral studies, Unnur has been involved in teaching at the Faculty of Pharmacy at the University of Iceland. Unnur's parents are Jónína Steingrímsdóttir and Þorsteinn Helgason. Her husband is Gunnar Geir Hinriksson, and they have two children together, Karólínu Eddu and Harald Stein.