Background: Recent studies showed a high prevalence of monoclonal gammopathy (MG) in patients with thrombotic microangiopathy (TMA) aged over 50 years and suggested that complement dysregulation is pivotal for the disease to develop. Here, we studied this premise in seven patients with TMA and coexisting MG.
Methods: Patients with TMA on kidney biopsy and/or peripheral blood were recruited from the prospective COMPETE cohort (NCT04745195) and Limburg Renal Registry. Patients were screened for complement dysregulation, including genetics/factor H autoantibodies (FHAA) and functional ex vivo testing on microvascular endothelial cells.
Results: Seven (8%) out of 84 patients with TMA presented with a coexisting MG. MG clustered in patients aged over 50 years (n/N = 6/32, 19%). C4 and/or C3 levels were low in three patients, while four patients presented with normal complement levels. None of the patients carried rare variants in complement genes. Massive ex vivo C5b9 formation on the endothelium was noted in one patient; purified IgG from this patient caused massive ex vivo C5b9 formation via the alternative pathway of complement activation, pointing to complement dysregulation in the fluid phase. Kidney biopsies from other nephropathies linked to MG rarely exhibited concurrent TMA (n/N = 1/27, 4%).
Conclusions: MG clustered in patients with TMA aged over 50 years. TMA and coexisting MG represents a heterogeneous disease spectrum, including a small subset of patients who may present with complement dysregulation.
Keywords: clone-directed treatment; complement dysregulation; eculizumab; monoclonal gammopathy of renal significance; thrombotic microangiopathy.
© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.