Kidney Week

Abstract: PO2238

A Mutation in Complement Factor B Causing Massive Fluid-Phase Dysregulation of the Alternative Complement Pathway Can Result in Atypical Hemolytic Uremic Syndrome

Session Information

• Pathology and Lab Medicine: Basic
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Pathology and Lab Medicine

• 1601 Pathology and Lab Medicine: Basic

Authors

• Zhang, Yuzhou, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States

Yuzhou Zhang,

• Kremsdorf, Robin Amy, Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States

Robin Amy Kremsdorf,

• Sperati, John, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

John Sperati,

• Henriksen, Kammi J., Department of Pathology, University of Chicago, Chicago, Illinois, United States

Kammi J. Henriksen,

• Mori, Mari, Division of Genetic and Genomic Medicine, Nationwide Children’s Hospital, Columbus, Ohio, United States

Mari Mori,

• Goodfellow, Renee X., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States

Renee X. Goodfellow,

• Pitcher, Gabriella R., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States

Gabriella R. Pitcher,

• Ghiringhelli Borsa, Nicolo, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States

Nicolo Ghiringhelli Borsa,

• Taylor, Ronald P., University of Virginia School of Medicine, Charlottesville, Virginia, United States

Ronald P. Taylor,

• Nester, Carla Marie, Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States

Carla Marie Nester,

• Smith, Richard J., Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, United States

Richard J. Smith,

Introduction

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. Pathogenesis is driven most frequently by dysregulated cell-surface control of the alternative pathway (AP) of complement secondary to inherited and/or acquired factors.

Case Description

We present two unrelated aHUS patients (a 5-year-old female and a 55-year-old female) who presented with the classic signs of thrombotic microangiopathy associated with renal failure with the additional finding of an undetectable C3 level. Circulating levels of C5 and properdin were also low, consistent with over-activity of both the alternative and the terminal pathways of complement. Genetic testing identified a heterozygous novel variant in the complement factor B gene (CFB c.1101 C>A, p.Ser367Arg). Functional studies demonstrated strong fluid-phase C3 cleavage when normal and proband sera were mixed. Cell-surface C3b deposition was strongly positive when patient serum was supplemented with C3. In vitro control of C3 convertase activity could be restored with increased concentrations of factor H.

Discussion

CFB p.Ser367Arg is a gain-of-function pathogenic variant that leads to dysregulation of the AP in the fluid-phase and increased C3b deposition on cell surfaces. This report highlights the complexities of complement-mediated diseases like aHUS and illustrates the importance of functional studies to characterize variants of unknown significance and to gain insight into the disease phenotype.