Atypical Hemolytic-Uremic Syndrome: Genetic Basis, Clinical Manifestations, and a Multidisciplinary Approach to Management

Keval Yerigeri,1 Saurav Kadatane,2 Kai Mongan,3 Olivia Boyer,4 Linda LG Burke,5 Sidharth Kumar Sethi,6 Christoph Licht,7 Rupesh Raina8 1Department of Internal Medicine-Pediatrics, Case Western Reserve University/The MetroHealth System, Cleveland, OH, USA; 2Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; 3Northeast Ohio Medical University, Rootstown, OH, USA; 4Department of Pediatric Nephrology, Dialysis and Transplantation, Necker-Enfants Malades Hospital, MARHEA reference Center, Imagine Institute, Paris Cité University, Paris, France; 5aHUS Global Advocate with aHUS Alliance, Cape Elizabeth, ME, USA; 6Department of Pediatric Nephrology and Pediatric Renal Transplant Medicine, Kidney and Urology Institute, Medanta, The Medicity, Gurgaon, Haryana, India; 7Department of Paediatrics, Division of Nephrology, University of Toronto, Toronto, ON, Canada; 8Division of Pediatric Nephrology, Akron Children’s Hospital, Akron, OH, USACorrespondence: Rupesh Raina, Tel +1 216 401 7894, Email RRaina@akronchildrens.orgAbstract: Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) defined by the triad of hemolytic anemia, thrombocytopenia, and acute kidney injury. Microthrombi develop in the glomerular capillaries secondary to endothelial damage and exert shear stress on red blood cells, consume platelets, and contribute to renal dysfunction and failure. Per current understanding of pathophysiology, HUS is classified into infectious, secondary, and atypical disease. The most common etiology is infectious sequelae of Shiga toxin-producing Escherichia coli (STEC); other causative organisms include shigella and salmonella. Secondary HUS arises from cancer, chemotherapy, solid organ and hematopoietic stem cell transplant, pregnancy, or autoimmune disorders. Primary atypical hemolytic-uremic syndrome (aHUS) is associated with genetic mutations in complement and complement regulatory proteins. Under physiologic conditions, complement regulators keep the alternative complement system continuously active at low levels. In times of inflammation, mutations in complement-related proteins lead to uncontrolled complement activity. The hyperactive inflammatory state leads to glomerular endothelial damage, activation of the coagulation cascade, and TMA findings. Atypical hemolytic-uremic syndrome is a rare disorder with a prevalence of 2.21 to 9.4 per million people aged 20 years or younger; children between the ages of 0 and 4 are most affected. Multidisciplinary health care is necessary for timely management of its extra-renal manifestations. These include vascular disease of the heart, brain, and skin, pulmonary hypertension and hemorrhage, and pregnancy complications. Adequate screening is required to monitor for sequelae. First-line treatment is the monoclonal antibody eculizumab, but several organ systems may require specialized interventions and coordination of care with sub-specialists.Keywords: atypical hemolytic uremic syndrome, eculizumab, plasma exchange, complications, extra-renal manifestations

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