Atypical Form Of Hemolytic Uremic Syndrome Research Articles

Hypogammaglobulinemia in a child with atypical hemolytic-uremic syndrome

We present a unique clinical case of an atypical hemolytic-uremic syndrome in a child. The mutation in exon 6 of the CD46 gene (chr1:207940532G>C) leads to a homozygous or hemizygous missense substitution. An 8-year-old girl was urgently hospitalized with symptoms of hemorrhagic syndrome and acute kidney injury. The child from the second pregnancy with an aggravated obstetric anamnesis, the first operative labor at the 38th week, who has an aggravated genealogical anamnesis. Initially, the disease developed in the guise of gastroenterological pathology: the girl had dyspeptic disorders, most likely associated with pathology of carbohydrate metabolism, also frequent infectious diseases and a lag in physical development. From the age of 4 years, the girl suffered from persistent hypoalbuminemia, hypoproteinemia and hypogammaglobulinemia, requiring replacement therapy with intravenous immunoglobulins. She was repeatedly examined in gastroenterological departments in Yekaterinburg and Moscow in 2021-2023, but no data concerning protein-losing enteropathies or primary immunodeficiency was obtained. Also, the whole-exome sequencing with result validation hasn’t confirmed an inherited etiology of the presumed congenital immune error. However, a CD46 gene mutation, associated with the development of hemolytic-uremic syndrome in some publications, was identified in the study. The signs of thrombotic microangiopathy were preceded by fever of unspecified etiology: microangiopathic hemolysis, thrombocytopenia, hyperazotemia, C3 consumption, proteinuria, and macrohematuria; hypercholesterolemia, protein metabolism disorder, increased transaminases, ferritin were also noted. According to the ultrasound of the kidneys there were diffuse changes in the parenchyma, decreased velocity indices of blood flow in both renal arteries at all levels. Differential diagnosis was carried out with thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, antinuclear form of atypical hemolytic-uremic syndrome, viral and bacterial infections, systemic pathology, antiphospholipid syndrome, and hemoblastosis. The girl didn’t need a renal replacement therapy. When complement-blocking therapy with eculizumab was initiated on vital indications, the signs of the disease were gradually eliminated. The prolonged absence of nephropathy in the child may indicate the diversity of the CD46 gene’s functions and different phenotypic manifestation of its mutations. Analysis of literature sources and detection of CD46 “environment” genes (CYBA, LYST, ARPCIB) by full-exome sequencing suggest ambiguity and polymorphism of phenotypic manifestations of complement-mediated mutation.

Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases.

The human complement factor H-related protein-3 (FHR-3) is a soluble regulator of the complement system. Homozygous cfhr3/1 deletion is a genetic risk factor for the autoimmune form of atypical hemolytic-uremic syndrome (aHUS), while also found to be protective in age-related macular degeneration (AMD). The precise function of FHR-3 remains to be fully characterized. We generated four mouse monoclonal antibodies (mAbs) for FHR-3 (RETC) without cross-reactivity to the complement factor H (FH)-family. These antibodies detected FHR-3 from human serum with a mean concentration of 1 μg/mL. FHR-3 levels in patients were significantly increased in sera from systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica but remained almost unchanged in samples from AMD or aHUS patients. Moreover, by immunostaining of an aged human donor retina, we discovered a local FHR-3 production by microglia/macrophages. The mAb RETC-2 modulated FHR-3 binding to C3b but not the binding of FHR-3 to heparin. Interestingly, FHR-3 competed with FH for binding C3b and the mAb RETC-2 reduced the interaction of FHR-3 and C3b, resulting in increased FH binding. Our results unveil a previously unknown systemic involvement of FHR-3 in rheumatoid diseases and a putative local role of FHR-3 mediated by microglia/macrophages in the damaged retina. We conclude that the local FHR-3/FH equilibrium in AMD is a potential therapeutic target, which can be modulated by our specific mAb RETC-2.

Post-streptococcal glomerulonephritis associated with atypical hemolytic uremic syndrome: to treat or not to treat with eculizumab?

A 7-year-old male with poststreptococcal glomerulonephritis (PSGN) developed hemolytic uremic syndrome (HUS) and achieved remission. He was treated with eculizumab for 1 year. The eculizumab was discontinued and the patient remained in remission. This is the 10th reported case of PSGN associated with HUS. The histopathological feature observed at the 1-year follow-up was indistinguishable from the expected findings in an individual with healed PSGN without associated HUS. The relatively good prognosis in most prior cases and the absence of any reported recurrences strongly suggest that this form of atypical HUS does not warrant long-term eculizumab therapy.

Genetics of atypical hemolytic uremic syndrome (aHUS).

Hemolytic uremic syndrome (HUS) is a rare, life-threatening disease characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The atypical form of HUS (aHUS), representing 5 to 10% of cases, lacks the association with infection by Shiga toxin producing Escherichia coli strains that characterizes the commonest clinical presentation of HUS. In the majority of aHUS cases, the disease results from the complement-mediated damage to the microvascular endothelium because of inherited defects in complement genes or autoantibodies against complement regulatory proteins. Incomplete penetrance of aHUS in carriers of mutations is common to all aHUS-associated complement genes and it is now established that the overall genetic predisposition to aHUS of an individual results from the combination of different inherited factors. Moreover, the patient's genotype influences the clinical evolution, the response to plasma therapies, and the recurrence after transplantation. Here, we describe the genetic component of aHUS, the lessons that we have learned from the functional characterization of the aHUS-associated mutations, and the benefits of a comprehensive genetic analysis of the patients.

Atypical Hemolytic Uremic Syndrome

SummaryHemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The underlying genetic defect predicts the prognosis both in native kidneys and after renal transplantation. The successful trials of the complement inhibitor eculizumab in the treatment of atypical HUS will revolutionize disease management.