Journal of Clinical Medicine Review The Syndromes of Thrombotic Microangiopathy: A Critical Appraisal on Complement Dysregulation Sjoerd A. M. E. G. Timmermans 1,2,* and Pieter van Paassen 1,2 1 Department Nephrology and Clinical Immunology, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands; [email protected] 2 Department Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), 6229 HX Maastricht, The Netherlands * Correspondence: [email protected] Abstract: Thrombotic microangiopathy (TMA) is a rare and potentially life-threatening condition that can be caused by a heterogeneous group of diseases, often affecting the brain and kidneys. TMAs should be classified according to etiology to indicate targets for treatment. Complement dysregulation is an important cause of TMA that defines cases not related to coexisting conditions, that is, primary atypical hemolytic uremic syndrome (HUS). Ever since the approval of therapeutic complement inhibition, the approach of TMA has focused on the recognition of primary atypical HUS. Recent advances, however, demonstrated the pivotal role of complement dysregulation in specific subtypes of patients considered to have secondary atypical HUS. This is particularly the case in patients presenting with coexisting hypertensive emergency, pregnancy, and kidney transplantation, shifting the paradigm of disease. In contrast, complement dysregulation is uncommon in patients with other coexisting conditions, such as bacterial infection, drug use, cancer, and autoimmunity, among Citation: Timmermans, S.A.M.E.G.; other disorders. In this review, we performed a critical appraisal on complement dysregulation and van Paassen, P. The Syndromes of the use of therapeutic complement inhibition in TMAs associated with coexisting conditions and Thrombotic Microangiopathy: A outline a pragmatic approach to diagnosis and treatment. For future studies, we advocate the term Critical Appraisal on Complement complement-mediated TMA as opposed to the traditional atypical HUS-type classification. Dysregulation. J. Clin. Med. 2021, 10, 3034. https://doi.org/10.3390/ Keywords: thrombotic microangiopathy; atypical hemolytic uremic syndrome; complement; jcm10143034 hypertensive emergency; pregnancy; kidney transplantation; eculizumab Academic Editor: Lee Ann MacMillan-Crow 1. Integrated Discussion Received: 28 May 2021 Thrombotic microangiopathy (TMA) is a rare, potentially life-threatening condition Accepted: 6 July 2021 Published: 8 July 2021 that reflects tissue responses to severe endothelial damage caused by distinct disorders, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (HUS). Publisher’s Note: MDPI stays neutral Despite heterogeneity, TMAs typically manifest with consumptive thrombocytopenia, with regard to jurisdictional claims in microangiopathic hemolytic anemia, and ischemic organ damage, often affecting the brain published maps and institutional affil- and kidneys. TMAs should be classified according to etiology to indicate targets for iations. treatment (Figure1)[ 1,2]. For example, thrombotic thrombocytopenic purpura is caused by a severe deficiency of von Willebrand cleaving protease (also known as a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13)) [3], and thus treatment should restore ADAMTS13’s function. The term HUS, either atypical or not, has been used to define any TMA with a normal functional activity of ADAMTS13. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. HUS occurring on the background of complement dysregulation defines primary atyp- This article is an open access article ical HUS, indicating a diagnosis of exclusion [1]. Many of such patients present with rare distributed under the terms and variants in complement genes and/or autoantibodies that inhibit complement regulatory conditions of the Creative Commons proteins [4,5]. Primary atypical HUS is considered an orphan disease, with an incidence of Attribution (CC BY) license (https:// <1 per million population per year [6]. Most patients with HUS (i.e., ~90%) present with creativecommons.org/licenses/by/ coexisting conditions, assumed to be the etiologic factor of disease, and have been termed 4.0/). secondary atypical HUS (Figure1)[ 7]. Known coexisting conditions linked to secondary J. Clin. Med. 2021, 10, 3034. https://doi.org/10.3390/jcm10143034 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 19 present with coexisting conditions, assumed to be the etiologic factor of disease, and have been termed secondary atypical HUS (Figure 1) [7]. Known coexisting conditions linked to secondary atypical HUS are hypertensive emergency, pregnancy, kidney transplanta- tion, bacterial infections, drug use, cancer, autoimmunity, and hematologic stem cell transplantation (HSCT), among others. Recent advances, however, linked complement dysregulation to specific subtypes of so-called secondary atypical HUS and poor kidney J. Clin. Med. 2021, 10, 3034 outcomes [8–10]. Thus, the traditional atypical HUS-type classification2 ofis 19not absolute be- cause complement dysregulation can be present along the spectrum of HUS [11]. In the era of therapeutic complement inhibition [12–14], the challenge is to recognize patients atypical HUS are hypertensive emergency, pregnancy, kidney transplantation, bacterial withinfections, complement drug use, dysregulation cancer, autoimmunity, in the and earliest hematologic possible stem stage cell to transplantation prevent end-stage kidney disease(HSCT), among(ESKD). others. Recent advances, however, linked complement dysregulation to specificIn subtypesthis review, of so-called we performed secondary atypical a critical HUS appraisal and poor kidneyon complement outcomes [8 –dysregulation10]. and therapeuticThus, the traditional complement atypical HUS-typeinhibition classification in HUS pres is notenting absolute with because coexisting complement conditions and out- dysregulation can be present along the spectrum of HUS [11]. In the era of therapeutic line a pragmatic approach to diagnosis and treatment. We advocate to use the term com- complement inhibition [12–14], the challenge is to recognize patients with complement plement-mediateddysregulation in the earliest (C-)TMA possible to stagedefine to preventcases related end-stage to kidneycomplement disease (ESKD). dysregulation. Figure 1. 1.The The atypical atypical HUS-type HUS-type classification classification [1,2]. [1,2]. In this review, we performed a critical appraisal on complement dysregulation and therapeuticSecondary complement atypical inhibition HUS represents in HUS presenting the majority with coexisting of TMAs, conditions that is, ~ and90%; Shiga toxin- producingoutline a pragmatic E. coli (STEC)-HUS, approach to diagnosis thrombotic and treatment. thrombocytop We advocateenic purpura to use the (TTP), term and primary atypicalcomplement-mediated HUS are responsible (C-)TMA to definefor 6%, cases 3%, related and to3% complement of TMAs dysregulation.[7]. DGKE, diacylglycerol ki- Secondary atypical HUS represents the majority of TMAs, that is, ~90%; Shiga toxin- naseproducing epsilon.E. coli HSCT,(STEC)-HUS, hematopoietic thrombotic thrombocytopenicstem cell transplantation. purpura (TTP), and primary atypical HUS are responsible for 6%, 3%, and 3% of TMAs [7]. DGKE, diacylglycerol kinase 2.epsilon. Primary HSCT, Atypical hematopoietic HUS, stem a Prototypic cell transplantation. C-TMA 2. PrimaryThe complement Atypical HUS, system a Prototypic is an C-TMA ancient and conserved effector system involved in the defenseThe complementagainst pathogens system is anand ancient host and homeostasi conserveds, effector which system can involvedbe activated in the via the classic, lectin,defense and against alternative pathogens pathways and host homeostasis, (Figure 2A). which The can alternative be activated pathway via the classic, is continuously ac- tivelectin, through and alternative a mechanism pathways (Figure known2A). as The the alternative thick-over, pathway i.e., is continuouslyspontaneou actives hydrolysis of C3. Hostthrough cells, a mechanism including known the endothelium, as the thick-over, are i.e., pr spontaneousotected from hydrolysis the harmful of C3. Host effects of comple- cells, including the endothelium, are protected from the harmful effects of complement mentactivation activation by regulatory by regulatory proteins. proteins. InIn the the late late 1980s, 1980s, complement complement dysregulation dysregulation (i.e., factor (i.e., H factor deficiency) H deficiency) was found was found in twoin two brothers brothers with with (primary(primary atypical) atypical) HUS HUS [15]. [15]. Thereafter, Thereafter, a linkage a linkage study in study three in three fami- liesfamilies identified identified a variant a variant in in CFHCFH [16][16] locatedlocated in in the the C’-terminal-reduced C’-terminal-reduced factor factor H’s H’s binding binding to the endothelium [17]. At present, >600 variants in complement genes have to the endothelium [17]. At present, >600 variants in complement genes have been identi- been identified in primary atypical HUS [18], with a prevalence of >50% [4,5]. Rare fiedvariants in primary (i.e., minor atypical allele frequency HUS [18], of with <0.1%) a [prevalence19] in CFH, CFIof >50%, CD46 [4,5]., C3, andRareCFB variants (i.e., mi- norare ofallele particular frequency interest of [ 18<0.1%)]. CFH [19], CFI in, andCFHCD46, CFI,variants