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Complement Activation in Atypical Hemolytic Uremic

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Complement Activation in Atypical Hemolytic Uremic REVIEW ARTICLE | ARTIGO DE REVISÃO Complement activation in atypical hemolytic uremic syn- drome and scleroderma renal crisis: a critical analysis of pathophysiology Ativação de complemento em síndrome urêmica hemolítica atípica e crise renal por esclerodermia: uma análise crítica da fisiopatologia Authors ABSTraCT RESUMO Roman Zuckerman 1 Arif Asif 1 Scleroderma is an autoimmune disease A esclerodermia é uma doença autoimune Eric J. Costanzo 1 that affects multiple systems. While que afeta múltiplos sistemas. Embora os Tushar Vachharajani 2 pathophysiologic mechanisms govern- mecanismos fisiopatológicos que regem o ing the development of scleroderma are desenvolvimento da esclerodermia sejam relatively poorly understood, advances relativamente pouco compreendidos, os 1 Jersey Shore University in our understanding of the complement avanços em nossa compreensão do sistema Medical Center, Seton Hall- system are clarifying the role of comple- do complemento estão esclarecendo o papel Hackensack-Meridian School ment pathways in the development of das vias do complemento no desenvolvimen- of Medicine, Neptune, NJ, atypical hemolytic uremic syndrome and to da síndrome urêmica hemolítica atípica e USA. scleroderma renal crisis. The abundant da crise renal da esclerodermia. As abundan- 2 W.G. (Bill) Hefner VA Medical Center, Salisbury, similarities in their presentation as well tes semelhanças em sua apresentação, bem North Carolina, USA. as the clinical course are raising the possi- como o curso clínico, estão aumentando a bility of a common underlying pathogen- possibilidade de uma patogênese subjacente esis. Recent reports are emphasizing that comum. Relatórios recentes estão enfatizan- complement pathways appear to be the do que as vias de complemento parecem ser o unifying link. This article reviews the role link unificador. Este artigo analisa o papel do of complement system in the development sistema do complemento no desenvolvimen- of atypical hemolytic uremic syndrome to da síndrome urêmica hemolítica atípica e and scleroderma renal crisis, and calls for da crise renal na esclerodermia, e exige maior heightened awareness to the development conscientização para com o desenvolvimento of thrombotic angiopathy in patients with da angiopatia trombótica em pacientes com scleroderma. esclerodermia. Keywords: Complement Activation; Palavras-chave: Ativação de Complemen- Scleroderma, Systemic; Acute Kidney In- to; Esclerodermia, Sistêmica; Lesão renal jury. aguda. INTrODUCTiON are skin thickening, Raynaud phenom- enon, digital ulcers, pulmonary arterial Systemic sclerosis (SSc) or scleroderma is hypertension (PAH), interstitial lung dis- an autoimmune heterogeneous disease in- ease (ILD), and renal disease. While PAH volving multiple systems and is classically and ILD are important causes of death in divided into limited, diffuse, and overlap patients with SSc, recent reports are em- forms of the disease.1 Three distinct patho- phasizing the development of thrombotic physiologic mechanisms continue to dom- microangiopathy (TMA) with its ensuing inate the disease process. These include, mortality (Table 1).4-11 1) a vascular injury leading to release of Submitted on: 05/12/2017. Approved on: 06/09/2017. vasoconstrictor mediators and tissue hy- SCLERODERmA AND THROmbOTiC miCROAN- poxia, 2) immunogenicity culminating in GiOPATHY production of antibodies, and 3) fibro- Correspondence to: TMAs are a group of disorders char- Roman Zuckerman. blast dysfunction resulting in increased E-mail: roman.zuckerman@ acterized by widespread microvascu- deposition of extracellular matrix.2-16 hackensackmeridian.org lar thrombosis, thrombocytopenia, and DOI: 10.1590/2175-8239-JBN-3807 Some features and manifestations of SSc 77 Complement system and scleroderma microangiopathic hemolytic anemia (MAHA).17 eventually leading to the membrane-attack complex.23 TMAs are traditionally classified into thrombotic C3 hydrolysis in plasma initiates the alternative path- thrombocytopenic purpura (TTP), atypical hemolytic way, leading to the deposition of C3b onto practically uremic syndrome (aHUS), and Shiga toxin-associated all plasma-exposed surfaces.23 Complement activa- HUS. In general, Shiga toxin-associated HUS occurs tion is controlled by various membrane-anchored and secondary to infection with Escherichia coli serotypes fluid-phase regulators.28 Factors B, D, and C3 par- 0157:H7, 0111:H8, 0103:H2, 0123, 026, or others ticipate in the generation of the alternative pathway that produce Shiga-like toxin. This form of TMA is C3 convertase (C3bBb), which is stabilized by factor not associated with SSc and is beyond the scope of P (properdin). C3 cleavage by the C3 convertases this paper. However, both aHUS and TTP have been and subsequent C5 cleavage by the C5 convertases reported with SSc.4,11,18-21 TTP is caused by the defi- results in the formation of C5a and C5b. The latter ciency of ADAMTS13 while aHUS results from an participates in the assembly of the membrane attack uncontrolled activation of the alternative pathway of complex (MAC; C5b-9, soluble terminal complement the complement system. 22-23 Histologically, on renal complex (sTCC)). MAC mediates target cell activa- biopsy, aHUS is indistinguishable from HUS caused tion, injury or lysis in a dose-dependent manner. The by toxin-producing bacteria or TTP. In acute cases, alternative pathway of the complement system is con- thrombi are identified within the glomerular capil- stitutively active and its activity is kept in check by laries, arterioles as well as arteries and are accompa- several soluble and membrane-bound complement nied by endothelial cell swelling or denudation. Over regulators.24 Common soluble complement regulatory time, there is thickening of glomerular capillary walls proteins include factor I, factor H, and C4-binding (double contour), loosening of mesangial architecture protein.22-24 Similarly, complement regulators also ex- (mesangiolysis) caused by accumulation of plasma ist on the surface of cells and include membrane cofac- proteins fibrin and fibrinogen, and the emergence of tor protein (MCP), decay accelerating factor (DAF), membranoproliferative pattern of injury.24 and complement regulator 1 (CR1) etc.24 Mutations Dysregulation of the alternative pathway of the of these regulatory proteins lead to an uncontrolled complement system leading to its uncontrolled acti- activation of the complement system causing endo- vation results in aHUS.22-27 The complement system is thelial injury and resulting in aHUS. Indeed, genetic one of the first defenses of the immune system to be abnormalities in complement system proteins have mobilized against a pathogen. Complement proteins been documented both in the familial and sporadic are produced in the liver and are present in blood, forms of aHUS.25 Multiple mutations in factors regu- lymph, and extracellular fluids. The three pathways lating the alternative complement pathway are found of the complement system (classic, lectin, and alter- in 40-60% of patients with aHUS.26,27 native) produce protease complexes termed C3 and In simple terms, three elements are needed to have C5 convertases that cleave C3 and C5 respectively, a high index of suspicion for aHUS. These include TABLE 1 SCLERODERMA RENAL CRISIS PATIENTS PRESENTING WITH THROMBOTIC MICROANGIOPATHY Plasma Diagnosis Reference # Age/gender Eculizumab ESRD Death therapy rendered 49 48 F Ye s No Ye s No HUS/TTP 58 35 F Ye s No No No TTP 52 73 M No No Ye s No HUS 53 48 F No No Ye s Ye s HUS 59 31 F Ye s No Ye s Ye s TTP 47 61 F No No Ye s No HUS 61 32 F Ye s No Ye s Ye s TTP 55 58 M Ye s No Ye s Ye s HUS 41 46 F Ye s Ye s No No aHUS 40 28 F No Ye s Ye s Ye s aHUS 78 Braz. J. Nephrol. (J. Bras. Nefrol.) 2018;40(1):77-81 Complement system and scleroderma thrombocytopenia, microangiopathic hemolytic ane- the acute phase relative to the time of sample collec- mia, and target organ injury.22 Thrombocytopenia tion. Additionally, the investigators did not measure with a platelet count < 150,000/µL or a 25% decline the amount of MAC deposition on surface of cells. A from the baseline, hemoglobin below 10g/dL, intra- possible explanation of low sTCC might also be its vascular hemolysis with elevated LDH and reduced quick removal from the circulation and prompt depo- haptoglobin, and schistocytes on peripheral smear all sition at the tissue level. However, one case report of a add to the diagnosis. Complement C3 level might be patient with SRC did demonstrate an elevated serum reduced with normal concentrations of C4, as well level of sTCC (along with decreased levels of both C3 as elevated C5a and C5b-9 complex.24 Recent stud- and C4).40 This patient was treated with eculizumab ies have demonstrated that the levels of membrane therapy demonstrating hematological remission. bound C5b-9 complex deposits on human microvas- Unfortunately, the patient died 8 weeks later, second- cular endothelial cells are increased in patients with ary to new onset heart failure.40 Another patient with aHUS and can be used as a marker for activation of scleroderma overlap syndrome (positive for PM-Scl the biological processes.29,30 However, these findings antibodies) presented with acute renal failure, throm- are neither sensitive nor specific for diagnosis and of bocytopenia, and microangiopathic hemolytic ane- limited prognostic value, with reduced levels of C3 mia.41 She was initially treated with plasmapheresis found in only in 30-50% of patients with certain for a presumed diagnosis of TTP. Because
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