A Caution Against the Use of C5b-9 Endothelial Assay to Support Eculizumab Therapy: A response to Maritati et al.: “Eculizumab first” in the management of posttransplant thrombotic microangiopathy

In their recent study Maritati and colleagues reported 45 patients with early onset TMA after kidney transplantation.[1Maritati F. et al.Eculizumab First" in the Management of Posttransplant Thrombotic Microangiopathy.Kidney Int Rep. 2024; (in press)Abstract Full Text Full Text PDF Scopus (0) Google Scholar] Using serum of these patients an increased C5b-9 deposition on endothelial cells was observed in 84%. The authors suggest that these positive test results support the effective use of eculizumab. We caution against such conclusion. Initially, it was hoped that the ex-vivo complement assay would allow to evaluate the presence of factors in serum that augment complement activation on endothelial cells, and to identify patients with (risk of) TMA caused by complement dysregulation. Later studies showed positive test results in patients with secondary TMA (STEC-HUS, sepsis).[2Galbusera M. et al.An Ex Vivo Test of Complement Activation on Endothelium for Individualized Eculizumab Therapy in Hemolytic Uremic Syndrome.Am J Kidney Dis. 2019; 74: 56-72Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Fernández S. et al.Distinctive Biomarker Features in the Endotheliopathy of COVID-19 and Septic Syndromes.Shock. 2022; 57: 95-105Crossref Scopus (37) Google Scholar] The study of Maritati, which included patients with secondary TMA (no pathogenic genetic complement gene variants in 96% of patients), underlines the poor specificity of the test for identifying patients with underlying complement dysregulation. Moreover, we caution against the use of the test in kidney transplant patients. We recently showed positive test results in stable kidney transplant patients, not known with aHUS and without TMA.[4Duineveld C. et al.Ex Vivo Test of Complement Dysregulation in Atypical Hemolytic Uremic Syndrome Kidney Transplant patients: A Pilot Study.Kidney Int Rep. 2024; 9: 145-151Abstract Full Text Full Text PDF Scopus (0) Google Scholar] It would have been enlightening if the authors had used a control group with kidney transplant patients without TMA. Lastly, a positive test result should not be used to guide decisions toward the use of eculizumab. As mentioned above, the test is often positive in patients with STEC-HUS, a condition with unproven added valued of eculizumab.[5Garnier A. et al.Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial.J Am Soc Nephrol. 2023; 34: 1561-1573Crossref Scopus (6) Google Scholar] Further studies of the ex-vivo C5b-9 assay, especially in kidney transplant patients, are needed. Response to "A CAUTION AGAINST THE USE OF C5B-9 ENDOTHELIAL ASSAY TO SUPPORT ECULIZUMAB THERAPY"Kidney International ReportsPreviewWe would like to thank Dr. Duineveld and colleagues for showing interest in our article titled "Eculizumab first" in the management of posttransplant thrombotic microangiopathy [1], by highlighting the role of the ex-vivo C5b-9 assay in the evaluation of disease activity. Full-Text PDF Open Access