GENETIC AND PHENOTYPIC PROFILE OF PEDIATRIC PATIENTS WITH ATYPICAL HEMOLYTIC-UREMIC SYNDROME
Authors: Emirova Kh.M. ,   Russian University of Medicine of the Ministry of Healthcare of Russia, Moscow, Russia, Krasko O.V. , Abaseyeva T.Yu. , Pankratenko T.E. , Muzurov A.L. , Vakhitov V.K. , Soboleva M.K. , Shavkin A.L. , Lupan I.N. , Albot V.V. , Ledenko L.A. , Makarova T.P. , Kudlay D.A. , Zaytseva O.V. , Shumeyko N.K. , Orlova O.M. , Generalova G.A. , Mstislavskaya S.A. , Popa A.V. , Kvaratskheliya M.V. , Shironina N.V. , Shatalov P.A. , Avdonin P.V. , Avdonin P.P. ,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   United Institute of Informatics Problems (UIIP) with the National Academy of Sciences of the Republic of Belarus, Minsk, Republic of Belarus,   Russian University of Medicine of the Ministry of Healthcare of Russia, Moscow, Russia,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   M.F. Vladimirsky Moscow Oblast Regional Scientific and Research Clinical Institute (MONIKI), Moscow, Russia,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   Russian Medical Academy for Continuous Professional Education, Moscow, Russia,   Kazan State Medical University, Kazan, Republic of Tatarstan, Russia,   Novosibirsk State Medical University, Novosibirsk, Russia,   Saint Petersburg City Municipal Children's Multidisciplinary Clinical Specialized Center of High Medical Technologies, Saint Petersburg, Russia,   Medical School of Additional Professional Education with the South Ural State Medical University (National Research University), Chelyabinsk, Russia,   Irkutsk State Medical Academy of Postgraduate Education, Branch of the Russian Medical Academy for Continuous Professional Education, Irkutsk, Russia,   Krasnodar Krai Regional Specialized Children's Clinical Hospital, Krasnodar, Krasnodar Krai, Russia,   Kuban State Medical University, Krasnodar, Krasnodar Krai, Russia,   Kazan State Medical University, Kazan, Republic of Tatarstan, Russia,   I.M. Sechenov First Moscow State Medical University, Moscow, Russia,   M.V. Lomonosov Moscow State University, Moscow, Russia,   National Research Center Institute of Immunology of the Russian Federal Biomedical Agency, Moscow, Russia,   Russian University of Medicine of the Ministry of Healthcare of Russia, Moscow, Russia,   Russian University of Medicine of the Ministry of Healthcare of Russia, Moscow, Russia,   Russian University of Medicine of the Ministry of Healthcare of Russia, Moscow, Russia,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   Russian Medical Academy for Continuous Professional Education, Moscow, Russia,   Russian University of Medicine of the Ministry of Healthcare of Russia, Moscow, Russia,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   Pirogov Russian National Research Medical University, Moscow, Russia,   Russian University of Medicine of the Ministry of Healthcare of Russia, Moscow, Russia,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   Russian University of Medicine of the Ministry of Healthcare of Russia, Moscow, Russia,   Saint Vladimir Moscow City Children's Clinical Hospital, Moscow, Russia,   National Medical Radiology Research Center, Obninsk, Kaluga Oblast, Russia,   Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, Russia,   Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow, Russia
Published: August 2024

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease caused by dysregulation of the alternative complement pathway as a result of mutations in complement genes or the formation of antibodies (AB) to some of the complement factors. Identification of the gene mutations incidence and the corresponding phenotypic features in pediatric patients with aHUS in Russia is aimed at improving the diagnosis and prognosis of the disease as well as treatment tactics planning for patient management. The purpose of this research was to determine the patterns of progression, prognosis and outcomes of aHUS in children depending on their genetic profile. Materials and methods used: the Article represents data from a retro- and prospective analyses of the characteristics of the course of aHUS in 172 children depending on their genetic profile performed in Jan. 2012-Feb. 2022. The sporadic form of aHUS was diagnosed after exclusion of the other forms of thrombotic microangiopathy (TMA), the familial form (in cases with the familial records), the acquired (CFH-Ab HUS) in cases with AB increase to factor H. AutoAb against factor H was determined by enzyme-linked immunosorbent assay (ELISA-VIDITEST anti-complement factor H). The search for mutations (n=167) was carried out using Next-generation Sequencing (NGS) and Sanger sequencing methods. Results: the sporadic form of aHUS was diagnosed in 96.9% of cases, familial in 3.1% and CFH-Ab HUS in 23.8%. The genetic nature of aHUS was confirmed in 53.4% of cases. Pathogenic mutations were detected in 8.6% of cases, probably pathogenic in 42.8% and those with unclear clinical significance in 46.8%. The complement genes mutations were detected in 88.5% of cases and mutations of genes not related to the complement system (ADAMTS13, DGKE, INF2) in 11.5%. The most frequently identified mutations were in the CFH (17.1%), C3 (12.9%) and CD46 (12.9%) genes and less frequently in CFI (7.1%), THBD (5.7%), CFHR5 (5.7%) and CFB (1.4%). In children with CFH-Ab HUS, the CFHR1/CFHR3 deletion was detected in 87.8% of cases, including in 19.4% in combination with mutations of unknown clinical significance. Multiple organ failure syndrome had developed in 77.8% of cases in children with pathogenic/probably pathogenic mutations, in 85.3% in patients with mutations of unknown clinical significance, in 91.8% in patients without mutations and in 83.3% in patients with CFHR1/CFHR3 deletion. Chronic kidney disease (CKD) stages 3 to 5 in sporadic/familial aHUS, regardless of genetic profile, had counted for 14.5% and 16.7% in CFH-Ab HUS. Lethal outcome occurred in 4.3% of cases in the presence of mutations, in 4.9% in the absence of mutations and in 2.8% in cases of CFHR1/CFHR3 deletion. Relapses of aHUS prior to the Eculizumab treatment had developed more often in the presence of CFHR1/CFHR3 mutations and deletion in comparison with children without mutations (31.4% v. 13.1%, p=0.0313 and 44.4% v. 13.1%, p= 0.004). Relapse of aHUS after discontinuation of the Eculizumab therapy had developed in 16.4% of cases. Risk factors for the relapse of aHUS were as follows: patient’s age above 12 months old at the time of the development of aHUS, severe arterial hypertension in the acute period, the use of Eculizumab at the fourth week after the onset of the disease and/or later, recurrent course of aHUS and the presence of CKD prior to the start of the Eculizumab therapy. Conclusion: The genetic profile of patients does not determine the severity and outcome of aHUS though it does affect the relapse rate. The prognosis and survival of patients with aHUS are determined by the severity of the acute period and the timeliness of the complement blocking therapy management.