Anticomplement Treatment in Atypical and Typical Hemolytic Uremic Syndrome

Abstract

The dissection of the pathogenic mechanisms of the various forms of the hemolytic uremic syndrome (HUS) has paved the way for the design of specific efficacious treatments. Such mechanistic approach led to a revolution in the management of atypical HUS with the use of the first-in class C5 blocker, eculizumab. The availability of this anticomplement drug has also raised unsettled questions regarding the cost or burden and optimal duration of therapy and its use in secondary HUS. The efficacy of eculizumab in Shiga toxin producing Escherichia coli-associated HUS is not to date established and the results of ongoing prospective studies are eagerly awaited. Nevertheless, the emergence of anticomplement therapies (eculizumab and other drugs in development) has transformed our approach of HUS.

Introduction

Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and acute kidney injury. It is one of the most impressive examples of how deciphering the specific mechanisms of the various forms of a syndrome can lead to a physiopathology-based efficient treatment. The demonstration in the late 1900s that postdiarrheal or typical HUS, the most common form of thrombotic microangiopathy (TMA) in children, was due to Shiga toxin (Stx) producing Escherichia coli (STEC), and that thrombotic thrombocytopenic purpura (TTP), one of the most frequent forms of TMA in adults, results from a severe deficiency in a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS 13), helped clinicians to distinguish TTP from HUS. Consequently, up to recent years, the term atypical HUS (aHUS) has been used to define any HUS related neither to STEC infection nor to severe ADAMTS13 deficiency. Thus it encompassed both primary forms of aHUS, and a variety of secondary aHUS related to infections (Streptococcus pneumoniae, human immunodeficiency virus), malignancies, drugs (cancer chemotherapy and calcineurin inhibitors), autoimmune diseases (systemic lupus erythematosus [SLE] and vasculitis), medical conditions (solid organ and hematopoietic stem cell transplantation) or metabolic disease (cobamamin C [cblC] defect). A major step forward was the demonstration over the 1998-2009 decade that primary aHUS was a disease of complement alternative pathway (CAP) dysregulation. Such dysregulation is linked to (1) loss-of-function variants in the genes of CAP regulatory proteins, complement factor H (CFH), membrane cofactor protein (MCP or CD46), complement factor I and thrombomodulin (THBD) or (2) gain-of-function variants in the genes of the C3 convertase components (complement factor B [CFB] and C3), or (3) anti-CFH inhibitory autoantibodies (review in [1]). CAP dysregulation impairs the physiological protection of endothelial cell surfaces against CAP activation-induced damage, leading to TMA (see review by R. Taylor of the mechanisms of aHUS in this issue and Ref. [1]).

More recently, young children with a hitherto unexplained aHUS were found to carry variants in the gene of diacylglycerol kinase ε (DGKE), an endothelial cell and podocyte protein with no direct link with the complement system, opening a new chapter of noncomplement-related forms of aHUS [2].

These breakthroughs led to various etiology-based classifications of HUS, proposed by nephrologists and hematologists (review in [1] and [3]). Anecdotically, the term aHUS is currently either restricted to aHUS cases not related to a coexisting disease or condition or specific infection [1], [4], or includes all TMAs except STEC-HUS and TTP [3]. More importantly, the demonstration that aHUS is a disease of CAP hyperactivation was the starting point for the use of the first clinically available complement inhibitor, eculizumab. In turn, the demonstration of eculizumab efficiency in aHUS reactivated or initiated studies of complement activation in various forms of HUS, including STEC-HUS, and raised the hope that eculizumab might be also efficient in these forms of HUS. In this review, we describe how complement-blockade therapy has revolutionized aHUS outcome and management, and discuss controversial issues of the optimal treatment duration in aHUS, and the potential efficacy of eculizumab in STEC-HUS and secondary aHUS.