{"id":6388,"date":"2026-10-19T09:48:51","date_gmt":"2026-10-19T09:48:51","guid":{"rendered":"https:\/\/phd.hi.is\/doktorsvorn\/doktorsvorn-i-lyfjafraedi-unnur-arna-thorsteinsdottir\/"},"modified":"2026-10-19T09:48:51","modified_gmt":"2026-10-19T09:48:51","slug":"doktorsvorn-i-lyfjafraedi-unnur-arna-thorsteinsdottir","status":"publish","type":"phd_defence","link":"https:\/\/phd.hi.is\/en\/doktorsvorn\/doktorsvorn-i-lyfjafraedi-unnur-arna-thorsteinsdottir\/","title":{"rendered":"Doktorsv\u00f6rn \u00ed lyfjafr\u00e6\u00f0i – Unnur Arna \u00deorsteinsd\u00f3ttir"},"content":{"rendered":"
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Fimmtudaginn 27. febr\u00faar 2025 ver Unnur Arna \u00deorsteinsd\u00f3ttir doktorsritger\u00f0 s\u00edna vi\u00f0 Lyfjafr\u00e6\u00f0ideild H\u00e1sk\u00f3la \u00cdslands. Ritger\u00f0in ber heiti\u00f0: UPLC-MS\/MS a\u00f0fer\u00f0ir til greiningar \u00e1 APRT-skorti og eftirlits me\u00f0 lyfjame\u00f0fer\u00f0 sj\u00fakd\u00f3msins. UPLC-MS\/MS assays for diagnosis of APRT deficiency and monitoring of pharmacotherapy.<\/strong><\/p>\n

Andm\u00e6lendur eru dr. Daniel T Holmes, kl\u00edn\u00edskur pr\u00f3fessor og deildarstj\u00f3ri vi\u00f0 St. Paul\u00b4s Hospital \u00ed Vancouver, og dr. Joe M. El-Khoury, d\u00f3sent vi\u00f0 Yale University School of Medicine.<\/p>\n

Umsj\u00f3narkennari og lei\u00f0beinandi voru Margr\u00e9t \u00deorsteinsd\u00f3ttir, pr\u00f3fessor og Run\u00f3lfur P\u00e1lsson, pr\u00f3fessor. Auk \u00feeirra s\u00e1tu \u00ed doktorsnefnd Vi\u00f0ar \u00d6rn E\u00f0var\u00f0sson, pr\u00f3fessor, J\u00f3n J\u00f3hannes J\u00f3nsson, pr\u00f3fessor og Matthew Lewis, varaforseti Bruker Daltonics.<\/p>\n

Elvar \u00d6rn Viktorsson, lektor og varadeildarforseti Lyfjafr\u00e6\u00f0ideildar, stj\u00f3rnar ath\u00f6fninni sem fer fram \u00ed H\u00e1t\u00ed\u00f0asal H\u00e1sk\u00f3la \u00cdslands og hefst kl. 13.30.<\/p>\n

\u00c1grip <\/strong><\/p>\n

Aden\u00ednfosf\u00f3r\u00edb\u00f3s\u00fdltransferasa (APRT)-skortur er sjaldg\u00e6fur, arfgengur p\u00far\u00ednefnaskiptasj\u00fakd\u00f3mur sem l\u00fdsir s\u00e9r fyrst og fremst \u00ed st\u00f3raukinni myndun 2,8-d\u00edh\u00fddrox\u00fdaden\u00edns (DHA) sem er mj\u00f6g torleyst \u00ed \u00fevagi og lei\u00f0ir til myndunar n\u00fdrnasteina og langvinns n\u00fdrnasj\u00fakd\u00f3ms. Me\u00f0fer\u00f0 me\u00f0 xant\u00edn ox\u00edd\u00f3reduktasa (XOR)-hemli, all\u00f3p\u00far\u00edn\u00f3li e\u00f0a feb\u00fax\u00f3stati, dregur \u00far \u00fatskilna\u00f0i DHA \u00ed \u00fevagi og h\u00e6gir \u00e1 framr\u00e1s langvinns n\u00fdrnasj\u00fakd\u00f3ms. \u00de\u00f6rf er \u00e1 \u00e1rei\u00f0anlegri magnbundinni t\u00e6kni, b\u00e6\u00f0i til greiningar \u00e1 APRT skorti og eftirlits me\u00f0 lyfjame\u00f0fer\u00f0.<\/p>\n

Markmi\u00f0 doktorsverkefnisins var a\u00f0 \u00fer\u00f3a, h\u00e1marka og gilda a\u00f0fer\u00f0ir me\u00f0 h\u00e1hra\u00f0av\u00f6kvaskilju sem tengd er tv\u00f6f\u00f6ldum massagreini (UPLC-MS\/MS) fyrir magngreiningu DHA og aden\u00edns \u00ed \u00fevagi og bl\u00f3\u00f0v\u00f6kva og all\u00f3p\u00farin\u00f3s, ox\u00fdp\u00farin\u00f3ls (virkt umbrotsefni all\u00f3p\u00farin\u00f3ls) og feb\u00faxostats \u00ed bl\u00f3\u00f0i.<\/p>\n

Tv\u00e6r UPLC-MS\/MS-a\u00f0fer\u00f0ir voru \u00fer\u00f3a\u00f0ar og gilda\u00f0ar samkv\u00e6mt st\u00f6\u00f0lu\u00f0um lei\u00f0beiningum, \u00f6nnur fyrir m\u00e6lingar \u00ed \u00fevagi og hin fyrir m\u00e6lingar \u00ed bl\u00f3\u00f0v\u00f6kva, og s\u00fdndu \u00fe\u00e6r n\u00e6gilegan \u00e1rei\u00f0anleika, n\u00e1kv\u00e6mni og st\u00f6\u00f0ugleika yfir sta\u00f0alk\u00farvubil efnanna.<\/p>\n

Kl\u00edn\u00edsk notkun \u00feessara m\u00e6lia\u00f0fer\u00f0a leiddi \u00ed lj\u00f3s markt\u00e6kt samband milli styrks DHA \u00ed bl\u00f3\u00f0v\u00f6kva, reikna\u00f0s gaukuls\u00edunarhra\u00f0a (r-GSH) og aldurs hj\u00e1 sj\u00faklingum sem voru ekki \u00ed me\u00f0fer\u00f0 me\u00f0 XOR-hemli. Ni\u00f0urst\u00f6\u00f0urnar benda til notagildis DHA-m\u00e6lingar til a\u00f0 meta upps\u00f6fnun efnisins hj\u00e1 sj\u00faklingum me\u00f0 APRT-skort, yfir breitt bil n\u00fdrnastarfsemi. Me\u00f0fer\u00f0 me\u00f0 XOR-hemli dr\u00f3 verulega \u00far styrk DHA b\u00e6\u00f0i \u00ed bl\u00f3\u00f0v\u00f6kva og \u00fevagi og var verkunin h\u00e1\u00f0 skammtast\u00e6r\u00f0 lyfjanna.<\/p>\n

Ni\u00f0urst\u00f6\u00f0ur ritger\u00f0arinnar veita mikilv\u00e6ga inns\u00fdn \u00ed meinal\u00edfe\u00f0lisfr\u00e6\u00f0i APRT-skorts og s\u00fdna fram \u00e1 samverkandi gagnsemi m\u00e6lia\u00f0fer\u00f0anna tveggja vi\u00f0 greiningu sj\u00fakd\u00f3msins og eftirlits me\u00f0 lyfjame\u00f0fer\u00f0 sj\u00faklinga.<\/p>\n

Abstract <\/strong><\/p>\n

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.<\/p>\n

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.<\/p>\n

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.<\/p>\n

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.<\/p>\n

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.<\/p>\n

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

Um doktorsefni\u00f0<\/strong><\/p>\n

Unnur Arna \u00deorsteinsd\u00f3ttir er f\u00e6dd \u00e1ri\u00f0 1989 \u00ed Kaupmannah\u00f6fn. H\u00fan \u00fatskrifa\u00f0ist af n\u00e1tt\u00farufr\u00e6\u00f0ibraut Menntask\u00f3lans vi\u00f0 Hamrahl\u00ed\u00f0 \u00e1ri\u00f0 2008. H\u00fan lauk B.Sc. pr\u00f3fi \u00ed l\u00edffr\u00e6\u00f0i vi\u00f0 H\u00e1sk\u00f3lann \u00ed Kaupmannah\u00f6fn \u00e1ri\u00f0 2012 og meistaran\u00e1mi \u00ed frumul\u00edffr\u00e6\u00f0i fr\u00e1 sama h\u00e1sk\u00f3la \u00e1ri\u00f0 2015. Unnur h\u00f3f doktorsn\u00e1m sitt vi\u00f0 H\u00e1sk\u00f3la \u00cdslands \u00e1ri\u00f0 2016. Ranns\u00f3knarverkefni\u00f0 hlaut styrk \u00far Ranns\u00f3knarsj\u00f3\u00f0i \u00edslands og Eimskipasj\u00f3\u00f0i H\u00e1sk\u00f3la \u00cdslands. Samhli\u00f0a doktorsn\u00e1mi hefur Unnur sinnt kennslu vi\u00f0 Lyfjafr\u00e6\u00f0ideild H\u00e1sk\u00f3la \u00cdslands. Foreldrar Unnar eru J\u00f3n\u00edna Steingr\u00edmsd\u00f3ttir og \u00deorsteinn Helgason. Eiginma\u00f0ur Unnar er Gunnar Geir Hinriksson og eiga \u00feau saman b\u00f6rnin Kar\u00f3l\u00ednu Eddu og Harald Stein.<\/p>\n<\/div><\/div>","protected":false},"featured_media":5742,"template":"","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"_phd_date_start":"2025-02-27T13:30:00+00:00","_phd_date_end":"2025-02-27T16:30:00+00:00","_phd_location":"A\u00f0albygging H\u00e1t\u00ed\u00f0asalur","_phd_admission":"A\u00f0gangur \u00f3keypis","_phd_thesis_title":"UPLC-MS\/MS a\u00f0fer\u00f0ir til greiningar \u00e1 APRT-skorti og eftirlits me\u00f0 lyfjame\u00f0fer\u00f0 sj\u00fakd\u00f3msins. 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