BRIEF REVIEW www.jasn.org Kidney Disease Caused by Dysregulation of the Complement Alternative Pathway: An Etiologic Approach † ‡ ‡ An S. De Vriese,* Sanjeev Sethi, Jens Van Praet,* Karl A. Nath, and Fernando C. Fervenza *Division of Nephrology, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium; and Divisions of †Anatomic Pathology and ‡Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota ABSTRACT Kidney diseases caused by genetic or acquired dysregulation of the complement and atypical postinfectious GN. aHUS is a alternative pathway (AP) are traditionally classified on the basis of clinical presentation thrombotic microangiopathy (TMA) typ- (atypical hemolytic uremic syndrome as thrombotic microangiopathy), biopsy appear- ified by the triad of AKI, microangiopathic ance (dense deposit disease and C3 GN), or clinical course (atypical postinfectious GN). hemolytic anemia, and thrombocytope- Each is characterized by an inappropriate activation of the AP, eventuating in renal nia, and clinically, it is often indistinguish- damage. The clinical diversity of these disorders highlights important differences able from thrombotic thrombocytopenic in the triggers, the sites and intensity of involvement, and the outcome of the AP purpura. The C3 glomerulopathies are dysregulation. Nevertheless, we contend that these diseases should be grouped as characterized by C3 accumulation, with disorders of the AP and classified on an etiologic basis. In this review, we define absent or scanty glomerular Ig deposition different pathophysiologic categories of AP dysfunction. The precise identification of on immunofluorescence examination.3 the underlying abnormality is the key to predict the response to immune suppression, This recently coined group includes both plasma infusion, and complement-inhibitory drugs and the outcome after transplan- C3 GN and dense deposit disease (DDD), tation. In a patient with presumed dysregulation of the AP, the collaboration of the which are discriminated from each other clinician, the renal pathologist, and the biochemical and genetic laboratory is very much by the location and appearance of the glo- encouraged, because this enables the elucidation of both the underlying pathogenesis merular deposits on electron micros- and the optimal therapeutic approach. copy.4,5 Atypical postinfectious GN refers to a clinical course where the diagnosis of J Am Soc Nephrol 26: 2917–2929, 2015. doi: 10.1681/ASN.2015020184 postinfectious GN is not followed by res- olution but by signs of persisting glomer- ular damage.6 Inappropriate activation or The complement system contributes in- complement cascade is initiated by the C5 modulation of the C3 convertase is the dispensably to immunologic homeostasis convertase and ultimately, generates the pathophysiologic process common to all in at least three major ways. First, this membrane attack complex inducing cell of these diseases and the one that instigates system is an essential part of innate im- lysis. The C3 convertase amplification tissue injury. munity that serves as the first-line defense loop requires rigorous control to prevent C3 glomerulopathies are typically char- against infections and nonmicrobial forms inadvertent tissue inflammation and dam- acterized by uncontrolled activation of the of stress. Second, it provides an interface age (Figure 2). Certain regulatory proteins AP in the fluid phase (i.e., in the circula- betweentheinnateandadaptiveimmunity, reside on the cell surface and provide cy- tion) and/or at tissue surfaces that and third, it contributes to immune sur- toprotection, whereas others exist in lack membrane–anchored complement veillance by clearing foreign or apoptotic plasma and limit fluid–phase complement cells.1,2 activation. The key stepinthe complement cascade Published online ahead of print. Publication date available at www.jasn.org. isthecleavageofC3toC3aandC3b affected by C3 convertase activity; the latter PATHOGENESIS Correspondence: Prof.AnS.DeVriese,Divisionof Nephrology and Infectious Diseases, AZ Sint-Jan may originate from the classic, lectin, or Brugge, Ruddershove, 10, B-8000 Brugge, Belgium. alternative pathways (APs) (Figure 1). The Kidney diseases caused by dysfunction of Email: [email protected] C3 convertases continuously cleave C3 in a theAPcompriseatypicalhemolyticuremic Copyright © 2015 by the American Society of powerful amplification loop. The terminal syndrome (aHUS), C3 glomerulopathies, Nephrology J Am Soc Nephrol 26: 2917–2929, 2015 ISSN : 1046-6673/2612-2917 2917 BRIEF REVIEW www.jasn.org The predilection for the kidney of disorders of the AP is incompletely un- derstood but may be related to the presence of the fenestrae continuously exposing the acellular subendothelial tissues to complement activators, a lower baseline expression of complement reg- ulators, and/or differences in the com- position of the glycocalix.10 Transitions between glomerulopathies included in this spectrum can occur during the disease course,11–14 after kid- ney transplantation,15,16 or among members of the same family,17 adding another layer of complexity to AP path- ophysiology. The cause of this potential variation between phenotypes is pres- ently unknown. The overactivation of the AP may be either constitutive or triggered. The AP is constitutively active owing to the slow spontaneous tick over of C3, leading to the formation of the AP C3 convertase. Agenetic Figure 1. The normal complement cascade. The complement system can be activated by the or acquired defect in the regulators of classic pathway, the lectin pathway, and the AP, all resulting in the formation of C3 convertases. complement activation may lead to un- The classic pathway is initiated by immune complexes that interact with C1q, ultimately leading totheformationoftheclassic pathwayC3convertaseC4bC2a.Thelectinpathway generatesthe checked spontaneous activation of the AP. same C3 convertase C4bC2a but is activated by the binding of mannose-binding lectins (MBLs) In some instances, the defect is not severe to carbohydrate moieties found primarily on the surface of microbial pathogens. The AP is enough to cause dysregulation in baseline capable of autoactivation by a mechanism called tick over of C3. Tick over occurs spontaneously circumstances, but a trigger may lead to 6 at a low rate, generating a conformationally changed C3, which is referred to as C3(H2O). overactivation of the complement pathway. C3(H2O) is capable of binding CFB, resulting in the cleavage of CFB by complement factor In these patients, sustained complement ac- D (CFD) and generating Ba and Bb and the formation of the AP C3 convertase C3 (H2O)Bb.Any tivation occurs in what otherwise would of the C3 convertases can cleave C3 to C3a and C3b. The C3b fragment can bind to CFB. After have been a self-limiting event. The eliciting the cleavage of CFB by CFD, the C3 convertase C3bBb is formed. This C3 convertase cleaves condition is most often an infection, a well fi more C3 to C3b to generate even more C3 convertase in a powerful ampli cation loop, re- known trigger for aHUS. A similar mecha- sulting in the full activation of the complement system. The plasma protein properdin stabilizes nism likely is at play in the C3 glomerulo- C3bBb and provides a platform for its in situ assembly on microbial surfaces, apoptotic cells, and malignant cells. C3b also initiates the terminal complement cascade by the formation of the pathies. In patients originally diagnosed C5 convertase through association with either of the C3 convertases (C4bC2aC3b or with postinfectious GN, AP abnormalities C3bBbC3b). The C5 convertase then cleaves C5 to C5a and C5b. C5b subsequently binds to were detected, and subsequent biopsies C6, facilitating the binding of C7, C8, and C9 and culminating in the formation of the C5b-9 were consistent with C3 glomerulo- terminal membrane attack complex (MAC). The latter forms pores in the membrane of pathy.6,18,19 Other triggers include vaccina- pathogens and damaged self-cells, thus promoting cell lysis. C3a and C5a are anaphylatoxins tions, immunosuppressive or antineoplastic and among the most powerful effectors of complement activation capable of inducing che- drugs, oral contraceptives, pregnancy, and motaxis, cell activation, and inflammatory signaling. MASP, mannose-binding lectin–associated childbirth. The development of a monoclo- serine protease. nal gammopathy, possibly acting as an au- toantibody, may also be a precipitating regulators.7 The glomerular basement response (Figure 3).4,8 aHUS, however, event. membrane (GBM) represents such a sen- generally results from AP dysregulation The expression of disease may also be sitive surface that it exclusively depends at the level of the cell membrane with determined by the site of the defect in the on attached soluble regulators, such as impaired cell surface protection against AP.The presence of several defects may be complement factor H (CFH), for protec- complement activation.9 The microvas- required to instigate clinical disease, which tion. As a consequence, continuous de- cular endothelium is targeted generally, was illustrated by the finding of genetic position of C3 and complement debris and the renal microvascular endothelium abnormalities in clinically unaffected rel- within the GBM occurs, with attendant is targeted particularly, thereby leading atives. Such combinations include more glomerular injury and a proliferative to a TMA4 (Figure 4). than one mutation,20 amutationand 2918 Journal of the American Society