Epidemiology, Outcomes, and Complement Gene Variants in Secondary Thrombotic Microangiopathies

Abstract

Background The identification of complement defects as major drivers of primary atypical hemolytic uremic syndrome (HUS) has transformed the landscape of thrombotic microangiopathies (TMAs), leading to the development of targeted therapies and better patient outcomes. By contrast, little is known about the presentation, genetics, and outcomes of TMA associated with specific diseases or conditions, also referred to as secondary TMA. Methods In this study, we assessed the relative incidence, clinical and genetic spectra, and long-term outcomes of secondary TMA versus other TMAs in consecutive patients hospitalized with a first episode of TMA from 2009 to 2019 at two European reference centers. Results During the study period, 336 patients were hospitalized with a first episode of TMA. Etiologies included atypical HUS in 49 patients (15%), thrombotic thrombocytopenic purpura (TTP) in 29 (9%), shigatoxin-associated HUS in 70 (21%), and secondary TMA in 188 (56%). The main causes of secondary TMA were hematopoietic stem-cell transplantation (n=56, 30%), solid-organ transplantation (n=44, 23%), and malignant hypertension (n=25, 13%). Rare variants in complement genes were identified in 32 of 49 patients (65%) with atypical HUS and eight of 64 patients (13%) with secondary TMA; pathogenic or likely pathogenic variants were found in 24 of 49 (49%) and two of 64 (3%) of them, respectively (P < 0.001). After a median follow-up of 1157 days, death or kidney failure occurred in 14 (29%), eight (28%), five (7%), and 121 (64%) patients with atypical HUS, TTP, shigatoxin-associated HUS, and secondary TMA, respectively. Unadjusted and adjusted Cox regressions showed that patients with secondary TMA had the highest risk of death or kidney failure (unadjusted hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.85 to 6.07; P < 0.001; adjusted HR, 4.11; 95% CI, 2.00 to 8.46; P < 0.001; considering atypical HUS as reference). Conclusions Secondary TMAs represent the main cause of TMA and are independently associated with a high risk of death and progression to kidney failure.

Hemolytic Uremic Syndrome

“…One third of patients with secondary thrombotic microangiopathy underwent plasma exchanges, and a small minority (4%) received eculizumab, when there is no definite proof of the efficacy of the former or the latter in this type of thrombotic microangiopathy. 3 The study by Werion et al is in keeping with previously published data regarding secondary thrombotic microangiopathy/HUS. 4,6,7 The design of the study and its results illustrate the difficulties in defining secondary thrombotic microangiopathy/ HUS.…”

“…The article by Werion et al 3 in this issue of CJASN is a timely reminder of many remaining unresolved questions in the field of HUS. The authors retrospectively analyzed the causes and outcomes of 336 consecutive adult patients with a first episode of thrombotic microangiopathy seen in two reference centers in Belgium.…”

“…One third of patients with secondary thrombotic microangiopathy underwent plasma exchanges, and a small minority (4%) received eculizumab, when there is no definite proof of the efficacy of the former or the latter in this type of thrombotic microangiopathy. 3…”

Response to “A Caution Against the Use of C5B-9 Endothelial Assay to Support Eculizumab Therapy”

“…In addition, several published findings showed that C5b-9 formation assay is positive in patients with secondary forms of acute TMA. 3 , 4 , 5 The above studies document that endothelial complement dysregulation occurs also in TMA forms in which the environmental trigger or the underlying disease play a stronger role in inducing endothelial injury and complement activations than the genetic background. By the way, rare complement gene variants have been reported in 10%–40% of patients with secondary TMA.…”

“…The capability of the ex vivo C5b-9 formation assay to evaluate the presence of factors in serum that augment complement activation on endothelial cells, and to identify patients with TMA caused by complement dysregulation is in fact supported by several publications from different independent groups, including Giuseppe Remuzzi in Bergamo, 2 , 3 S.A.M.E.G. Timmermans in Maastricht 4 , 5 and Marta Palomo in Barcelona. 6 , 7 …”