#3701 Genetic insights delCFHR3-1 linked to de novo thrombotic microangiopathy in kidney transplant rfecipients

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Abstract Background and Aims The complement system's overactivation typically occurs during transplantation and in the post-transplant phase. Indeed, donor and recipient characteristics, various drugs (mTOR inhibitors, CNIs), viral infections and ischemia-reperfusion injury contribute to different levels of complement activation in this particular setting. Overactivation of the complement system can expose some patients to developed thrombotic microangiopathy (TMA), especially in the case of genetic background predisposition. The Post-transplant de novo TMA incidence ranges from 5% to 20%, representing an open challenge for clinicians. Our study aimed to determine whether patients who developed post-transplant TMA exhibit complement gene variants and whether these variants correlate with the phenotype and the graft outcome. Method We evaluated 7 patients who developed de novo post-transplant TMA between 2022 and 2023. Complement genes variations were screened by Next Generation Sequencing , and Multiplex Ligation Probe Amplification (MLPA). Clinical and biochemical data at the time of onset (T0) and during the follow-up (T1) (median time of 1 year) were collected from patients' records. Correlation between genetic variation and clinical presentation were evaluated. Results In the studied population, 71.4% were female and 28.6% were male, with an average age at transplantation of 49 years; 6/7 patients received transplants from deceased donors. Thrombotic microangiopathy (TMA) developed, on average, after a duration of 61.2 months post-transplant. All patients received the same immunosuppressive therapy (MMF + FK + steroids). Genetic analysis revealed that all patients who developed de novo TMA post-transplant exhibited a delCFHR3-1, with 6 of these being heterozygous and 1 homozygous. Additionally, patient 7 was found to carry a heterozygous deletion affecting SCR 14 of CFH (NM_000186.4; c.2422_2427del). None of the patients exhibited anti-CFH antibodies, which are associated with the presence of the deletion variant in the literature. Serological tests for CH50 and AP50 were within normal ranges, confirming their limited utility in the diagnostic phase, as TMA is a condition characterised by complement dysregulation at the endothelial level rather than in serum. Forty-two percent of patients experienced graft loss. Among these, only one patient had received anti-C5 therapy. The remaining four patients achieved complete resolution of TMA. Of these, one received a C5 inhibitor during the acute phase, while another was treated with plasma therapy. Additionally, one patient in this group exhibited a form of thrombotic microangiopathy (TMA) that appeared to be triggered by treatment with fluoroquinolones. In this last case the complete resolution of the haematological condition and organ damage was observed upon discontinuation of the offending agent. Conclusion The delCFHR3-1 is associated with post-transplant TMA in our study cohort. Although the deletion is regarded as a polymorphic variant, our research suggests the utility of further exploring the role of this variant in complex scenarios such as transplantation, where complement activation is elevated. Further studies are warranted to elucidate the underlying mechanisms and therapeutic implications.

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