Revisiting Genetics of Atypical Hemolytic Uremic Syndrome: Lessons from Recent Review

Atypical Hemolytic Uremic Syndrome: A Review of Complement Dysregulation, Genetic Susceptibility and Multiorgan Involvement This article provides a comprehensive overview of atypical hemolytic uremic syndrome (aHUS), emphasizing recent advances in diagnosis and management. It begins by outlining primary and secondary thrombotic microangiopathies (TMAs) and clarifies the diagnostic distinctions among thrombotic thrombocytopenic purpura, typical HUS, aHUS, and secondary HUS. The paper summarizes current knowledge of aHUS pathophysiology and details its diverse clinical manifestations. Therapeutic strategies are reviewed extensively, particularly the use of complement inhibitors such as eculizumab and ravulizumab. The article also offers insight into emerging therapies, including agents targeting the membrane attack complex, factor B, factor D, and other components of the complement pathway.[1] Atypical Hemolytic Uremic Syndrome Walsh and Kavanagh give a detailed description of the genetic mechanisms underlying aHUS and explain the key genetic contributors. Since the complement proteins are primarily synthesized in the liver, renal transplantation alone does not correct the underlying cause and historically has led to poor clinical outcomes. Additional genetic causes of TMA are discussed, including inborn errors of Vitamin B12 metabolism due to biallelic variants in MMACHC and TMAs linked to defects in RNA processing involving EXOSC3 and EXOSC5. The article concludes by summarizing insights from a recent international HUS forum, which identified persistent uncertainties and priorities for future research.[2] Annual Trends in Atypical Hemolytic Uremic Syndrome Management in Japan and Factors Influencing Early Diagnosis and Treatment: A Retrospective Study This study investigated national trends in the early diagnosis and management of aHUS in Japan, recognizing that early detection remains difficult despite established guidelines. Using data from the 2011 to 2020 Diagnosis Procedure Combination database, the researchers identified 3096 cases coded as HUS, of which 217 were confirmed as aHUS based on documented diagnosis and treatment with either eculizumab or plasma exchange (PE). The analysis revealed no significant change in the annual number of confirmed aHUS cases over the study period. Three comparative analyses were conducted. Across analyses, the findings consistently showed that early initiation of either PE or eculizumab was associated with shorter hospital stays and lower medical costs.[3] Terminal Complement Inhibition in Atypical Hemolytic Uremic Syndrome: A Single-centre Experience This retrospective observational study evaluated 27 patients diagnosed with aHUS at the “Fundeni” Clinical Institute between January 2017 and January 2025. All patients exhibited at least one extrarenal manifestation. The study aimed to characterize clinical presentation, genetic findings, and outcomes. Genetic testing was performed in 23 patients, revealing variants in 74% of them. Variants in the CFH/CFHR gene cluster were most common (39%). Notably, CFI variants appeared more frequently than expected. Treatment with anti-C5 therapy proved effective and safe. This study provides the first comprehensive Romanian data on aHUS presentation, genetics, and response to anticomplement therapy.[4] Navigating Pediatric Atypical Hemolytic Uremic Syndrome: A Two-Year Case Series From Eastern India This is a two-year case series from Eastern India that aimed to characterize the clinical and genetic spectrumof pediatricaHUSand evaluate responses to plasma-based therapy in a resource-limited setting. All patients were diagnosed with HUS and received plasma-based therapy and immunosuppression. Genetic testing revealed homozygous deletion of CFHR1/CFHR3 in two patients, a heterozygous CFHR1/CFHR3 deletion in one, and a homozygous missense variant in CFH in one. Anti–factor H antibodies were detected in three patients. Hematological remission was achieved in 71%, however, complete renal recovery occurred in only 43%, while 29% progressed to chronic kidney disease. The findings highlight the need for early diagnosis and timely plasma exchange.[5] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.