MBL2 deficiency and IgA Nephropathy in transplant patients: Is complement inhibition always beneficial?

IgA nephropathy (IgAN) is a leading cause of End-Stage Renal Disease, with kidney transplantation as the preferred treatment, although with unpredictable and diverse outcomes. Mannose-binding lectin (MBL), a key component of the lectin pathway (LP), is associated with IgAN, and both excessive and deficient levels may exacerbate the disease. Genetic variants in MBL2 affect MBL serum levels and function, potentially influencing graft outcomes. We investigated correlations between MBL2 variants, MBL levels, complement system activation, and graft survival in 64 IgAN transplant recipients. The combined impact of MBL2 alleles and delCFHR3-1 status was also evaluated. Patients with the MBL2 "O" allele exhibited significantly lower MBL serum levels (p = 0.0013) and reduced event-free survival (p = 0.024) compared to wild-type "A" allele carriers. This deficiency was associated with increased alternative pathway (AP) activity, suggesting that enhanced complement activation contributes to allograft dysfunction. These findings highlight the role of AP on graft survival of IgAN transplant patients. Therefore, genotyping for delCFHR3-1 and the MBL2 "O" allele and MBL level assessment could provide prognostic insights. Identifying at-risk patients may enable personalised strategies, such as targeting a specific complement pathway, to improve post-transplant outcomes and extend graft survival, thus challenging the universal benefit of complete complement inhibition in this population.