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Kidney Week

Abstract: TH-PO803

Familial Pregnancy-Associated aHUS and Acute Heart Failure Successfully Treated with Eculizumab

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Java, Anuja, Washington University in St. Louis, Saint Louis, Missouri, United States
  • Ren, Zhen, Washington University in St. Louis, Saint Louis, Missouri, United States
  • Motwani, Pooja, CARTI, Little Rock, Arkansas, United States
  • Atkinson, John P., Washington University in St. Louis, Saint Louis, Missouri, United States
Introduction

Atypical HUS is a rare thrombotic microangiopathy (TMA) characterized by anemia, thrombocytopenia (TP) and AKI. Mutations in genes encoding complement proteins have been identified in ~60% of patients. We report 3 sisters who developed aHUS after pregnancy. ADAMTS13 was normal in all.

Case Description

Sister 1: 25-yr-old Hispanic female (HF) presented 10 days postpartum (pp) in 2015 with anemia, TP, and AKI. Kidney biopsy showed a TMA which was treated with plasma exchange (PE) and steroids. Later she developed heart failure (HF) from mitral valve perforation requiring intubation, valve replacement & hemodialysis (HD). Eculizumab was initiated. Creatinine improved in 2 wk and HD was discontinued. Sister 2: 24-yr-old HF developed anemia, TP, and AKI 7 days pp in 2014, treated with PE. Creatinine deteriorated and HD was initiated. One year later, after the diagnosis in sister #1, aHUS was considered and eculizumab initiated. Creatinine improved and HD was discontinued after 2 years. Sister 3: 18-yr-old HF presented 7 days pp in 2006 with anemia, TP, and AKI. Kidney biopsy revealed a TMA which was nonresponsive to PE and HD was initiated. Course was complicated by HF due to severe mitral and tricuspid regurgitation. She was not treated with eculizumab since aHUS was not considered until after it was diagnosed in her two sisters (8 years later). Genetic testing for all 3: 1) Splice-site variant (c.287-2A>G) in membrane cofactor protein (MCP) known to be aHUS-associated; 2) A novel variant (G918E) in Factor H (FH) of uncertain significance; 3) A heterozygous variant (K441R) in Factor I, likely benign; 4) A heterozygous variant (N1050Y) in FH, likely benign. Our functional analysis for these variants reveals that the G918E is not secreted and leads to low FH levels. The N1050Y is normally secreted and has normal C3b and heparin binding properties. The K441R has normal secretion and activity. The splice-variant in MCP is expected to cause decreased expression of MCP leading to low levels.

Discussion

The sisters carry pathogenic mutations in both MCP and FH. It is unusual for patients with aHUS to carry multiple rare variants. Pregnancy was the trigger in this family (patients' paternal grandmother lost 10 of 12 pregnancies). Acute heart failure due to valvular disease is novel. Possible mechanism is thrombus formation followed by endocarditis.