Abstract

Atypical  hemolytic  uremic  syndrome  (aHUS)  is  a  chronic  genetically-mediated  systemic  disease  caused  by  uncontrolled  activation  of  the  alternative  complement  pathway  that  leads  to  generalized  thrombosis  of  the  microcirculatory  vessels  (complement-mediated  thrombotic microangiopathy, TMA). Plasma therapy was long considered the first-line treatment of aHUS. In the early 2000s, considerable progress in the understanding of aHUS pathophysiology  and  its  treatment  was  achieved,  leading  to  the  emergence  of  innovative  therapeutic approaches. An original drug of eculizumab has shown high efficacy in aHUS patients  associated  with  hematological  remission,  including  renal  function  recovery  in  some cases.

Study purpose: To assess the efficacy and safety of the first Russian eculizumab biosimilar for the treatment of aHUS in adults.

Patients and methods: A clinical observation of one adult patient with aHUS was held.

Results: A 46-year-old patient has a history of hypertension since 2012 and maximum BP of 230/130 mm Hg. In 2016, newly diagnosed azotemia was identified (blood creatinine —140 μmol/L, GFR by EPI—54 mL/min/1.73 m2). In 2018, the patient suffered an acute cerebrovascular accident in the vertebrobasilar area. On the date of admission to the Almazov National Medical Research Center the blood test showed: creatinine —60 μmol/L (GFR by EPI —28 mL/min/1.73 m2), urea —11.52 mmol/L, LDH—130 U/L, complement system C3—1.32 g/L, ?4—0.37 g/L, haemoglobin—144 g/L, platelets—302*109/L; urinalysis showed: daily protein loss—2.6 g/day, RBC—0–1 per HPF. Taking into account the kidney damage, the renal fine-needle aspiration biopsy was performed, revealing histopathological findings  typical  of  chronic  thrombotic  microangiopathy,  arteriolar  arteriosclerosis  of extreme  severity  with  total  or  subtotal  luminal  occlusion,  extensive  secondary  perihilar  segmental glomerulosclerosis (27%) and global glomerulosclerosis (55%). According to the study results, the secondary genesis of TMA was ruled out, as well as STEC-HUS and  thrombotic  thrombocytopenic  purpura  (TTP),  systemic  diseases  (systemic  lupus  erythematosus,  antiphospholipid  syndrome  (APS),  and  systemic  sclerosis),  malignancies,  HIV  infection,  sepsis,  malignant  hypertension,  adverse  drug  events,  or  disseminated  intravascular coagulation (DIC). Plasma ADAMTS13 levels    were also assessed. Its activity was 64% (normal range 93–113%) of ADAMTS13 activity in the control plasma, thus the diagnosis of thrombocytopenic purpura was ruled out. Due to the absence of anti-CFH-antibodies, the antibody origin of aHUS was also ruled out.

To  assess  the  contribution  of  additional  factors  promoting  the  development  of  TMA,  the  polymorphism of haemostasis genes was studied to reveal homozygous genotypes of platelet collagen receptors (ITGA2: 807 ?/?), heterozygous genotypes of fibrinogen genes (FGB: 455 G/?), folate cycle enzymes (methylenetetrahydrofolate reductase (MTHFR: 677 C/T), methionine synthase (MTR: 2756 A/G (D919G)), responsible for a pronounced tendency towards hyperhomocysteinemia. In the clinical case the diagnosis of aHUS was obvious, which  was  supported  by  the  classical  symptom  cluster  of  TMA  and  histopathological  verification  in  the  absence  of  data  suggestive  of  other  pathological  conditions.  The peculiarity  of  this  clinical  case  is  the  late  diagnosis,  long-standing  course,  and  severity  (complications such as an acute cerebrovascular accident in the vertebrobasilar area, target lesions, kidneys in particular). Taking into account the primary diagnosis, treatment with a standard dose of eculizumab was initiated. After three months of treatment, the patient was switched to therapy with the first Russian eculizumab biosimilar. After the switch from the original drug, the therapy with the biosimilar continued a positive trend including a gradual decline in azotemia level (blood creatinine—115 μmol/L (GFR by EPI—65 mL/min/1.73 m2), blood urea—6.90 mmol/L), proteinuria (daily protein loss—0.6 g/day). BP was also normalized. No adverse events associated with the therapy were observed.

Conclusion: Based on the evidence obtained, the first Russian eculizumab demonstrated its high efficacy and safety for the treatment of an adult patient with aHUS.

Keywords

diagnosis, long-standing course, segmental glomerulosclerosis, global glomerulosclerosis, vertebrobasilar area, target lesions, kidneys