Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab.

TY - JOUR

T1 - Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab.

AU - Schmidtko, Jan

AU - Peine, Sven

AU - El-Housseini, Youssef

AU - Pascual, Manuel

AU - Meier, Pascal

PY - 2013

Y1 - 2013

N2 - Uncontrolled complement activation is central to the occurrence of atypical hemolytic uremic syndrome (aHUS) and can result in thrombotic microangiopathies (TMAs). These terms encompass a group of heterogenic inherited or acquired diseases that recent research suggests may be triggered by the complement cascade. Pathogenetic triggers of complement activation include immunologic disorders, genetics, infections, systemic diseases, pregnancy, drug administration, metabolic diseases, transplantation, or triggers of mixed cause. Hallmarks of aHUS and other TMAs include increased vascular endothelium thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, coagulation abnormalities, and vascular shear stress, whereas common end points of these mechanisms include hemolytic anemia, thrombocytopenia with microvascular infarction, and predisposition for decreased kidney function and other organ involvement. The central role of the complement cascade as a disease trigger suggests a possible therapeutic target. Eculizumab, a first-in-class humanized monoclonal anti-C5 antibody that has been successful in the treatment of paroxysmal nocturnal hemoglobinuria, a disorder of complement-induced hemolytic anemia, received approval for the treatment of aHUS in the United States and Europe in late 2011. We review the treatment of aHUS and other TMAs, focusing on the role of eculizumab, including its pharmacology, mechanism of action, and approved dosing recommendations and health economic considerations. Finally, the potential for future indications for eculizumab use in other complement-driven diseases is discussed.

AB - Uncontrolled complement activation is central to the occurrence of atypical hemolytic uremic syndrome (aHUS) and can result in thrombotic microangiopathies (TMAs). These terms encompass a group of heterogenic inherited or acquired diseases that recent research suggests may be triggered by the complement cascade. Pathogenetic triggers of complement activation include immunologic disorders, genetics, infections, systemic diseases, pregnancy, drug administration, metabolic diseases, transplantation, or triggers of mixed cause. Hallmarks of aHUS and other TMAs include increased vascular endothelium thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, coagulation abnormalities, and vascular shear stress, whereas common end points of these mechanisms include hemolytic anemia, thrombocytopenia with microvascular infarction, and predisposition for decreased kidney function and other organ involvement. The central role of the complement cascade as a disease trigger suggests a possible therapeutic target. Eculizumab, a first-in-class humanized monoclonal anti-C5 antibody that has been successful in the treatment of paroxysmal nocturnal hemoglobinuria, a disorder of complement-induced hemolytic anemia, received approval for the treatment of aHUS in the United States and Europe in late 2011. We review the treatment of aHUS and other TMAs, focusing on the role of eculizumab, including its pharmacology, mechanism of action, and approved dosing recommendations and health economic considerations. Finally, the potential for future indications for eculizumab use in other complement-driven diseases is discussed.

KW - Humans

KW - Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use

KW - Hemolytic-Uremic Syndrome/drug therapy

KW - Thrombotic Microangiopathies/drug therapy

KW - Humans

KW - Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use

KW - Hemolytic-Uremic Syndrome/drug therapy

KW - Thrombotic Microangiopathies/drug therapy

M3 - SCORING: Journal article

VL - 61

SP - 289

EP - 299

JO - AM J KIDNEY DIS

JF - AM J KIDNEY DIS

SN - 0272-6386

IS - 2

M1 - 2

ER -