Ex vivo C5b-9 Deposition Test to Monitor Complement Activity in Clinical and Subclinical Atypical Hemolytic Uremic Syndrome and in Transplantation-Associated Thrombotic Microangiopathy

Abstract

Biomarkers; C5 blockade; Complement system

Biomarcadors; Bloqueig C5; Sistema del complement

Biomarcadores; Bloqueo C5; Sistema del complemento

Introduction Atypical hemolytic uremic syndrome (aHUS) is a complement system (CS)–mediated ultrarare disease that manifests as thrombotic microangiopathy (TMA) with preferential small kidney vessels involvement. Transient CS activation is also observed in secondary TMA or in patients at risk of developing aHUS. There is no gold standard test to monitor disease activity; however, the ex vivo C5b-9 deposition test seems to be a good approach. Methods We assessed the C5b-9 deposition induced by serum samples of patients with aHUS (n = 8) and with TMA associated with kidney (n = 2), lung (n = 1) or hematopoietic stem cell (HSC) transplantation (HSCT, n = 2) during the acute phase of the disease or in remission. As control for transplant-associated TMA (TA-TMA), we analyzed samples of clinically stable kidney and HSC-transplanted patients without signs of TMA. In addition, we studied 1 child with genetic risk of aHUS during an acute infection. Results In the acute disease phase or in patients with disease activity despite C5 blockade, a significant increase of C5b-9 deposition was detected. In all patients with clinical response to C5 blockade but one, levels of C5b-9 deposition were within the normal range. Finally, we detected increased C5b-9 deposition levels in an asymptomatic child with genetic risk of aHUS when a concomitant otitis episode was ongoing. Conclusion The ex vivo C5b-9 deposition test is an auspicious tool to monitor CS activity in aHUS and TA-TMA. In addition, we demonstrate that the test may be useful to detect subclinical increase of CS activity, which expands the spectrum of patients that would benefit from a better CS activity assessment.

This study was funded with a research grant from Alexion and a grant from the Spanish Society of Nephrology. JL-R is recipient of a Rio Hortega grant from Instituto de Salud Carlos III (CM23/00213). The authors are recipients of research grants from Instituto de Salud Carlos III (AC22/00029, PI21/01292), Fundació la Marató de TV3 (202017-10, 202037-31 and 202133-30). The Nephrology and Transplantation group is part of the RICORS2040 network (RD21/0005/0031) and is recognized as a consolidated group by the Catalan Management Agency for University and Research Grants (2021 SGR 00883).